Amino compounds for treatment of immune and inflammatory disorders

ABSTRACT

Compounds, methods of use, and processes for making inhibitors of complement Factor D are provided comprising Formula I, I″ and I′″ or a pharmaceutically acceptable salt or composition thereof. The inhibitors described herein target Factor D and inhibit or regulate the complement cascade. The inhibitors of Factor D described herein reduces the excessive activation of complement.

BACKGROUND

An immune disorder occurs when the immune system is not performing in anormal manner. Inflammation is a protective response that involvesimmune cells, the immune system generally, blood vessels, and molecularmediators. A wide variety of medical disorders are caused by detrimentalimmune or inflammatory responses, or the inability of a cell to respondto a normal immune or inflammatory process.

The complement system is a part of the innate immune system which doesnot adapt to changes over the course of the host's life, but isrecruited and used by the adaptive immune system. For example, itassists, or complements, the ability of antibodies and phagocytic cellsto clear pathogens. This sophisticated regulatory pathway allows rapidreaction to pathogenic organisms while protecting host cells fromdestruction. Over thirty proteins and protein fragments make up thecomplement system. These proteins act through opsonization (enhancingphaogytosis of antigens), chemotaxis (attracting macrophages andneutrophils), cell lysis (rupturing membranes of foreign cells) andagglutination (clustering and binding of pathogens together).

The complement system has three pathways: classical, alternative andlectin. Complement Factor D plays an early and central role inactivation of the alternative pathway of the complement cascade.Activation of the alternative complement pathway is initiated byspontaneous hydrolysis of a thioester bond within C3 to produce C3(H₂O),which associates with Factor B to form the C3(H₂O)B complex. ComplementFactor D acts to cleave Factor B within the C3(H₂O)B complex to form Baand Bb. The Bb fragment remains associated with C3(H₂O) to form thealternative pathway C3 convertase C3(H₂O)Bb. Additionally, C3b generatedby any of the C3 convertases also associates with Factor B to form C3bB,which Factor D cleaves to generate the later stage alternative pathwayC3 convertase C3bBb. This latter form of the alternative pathway C3convertase may provide important downstream amplification within allthree of the defined complement pathways, leading ultimately to therecruitment and assembly of additional factors in the complement cascadepathway, including the cleavage of C5 to C5a and C5b. C5b acts in theassembly of factors C6, C7, C8, and C9 into the membrane attack complex,which can destroy pathogenic cells by lysing the cell.

The dysfunction of or excessive activation of complement has been linkedto certain autoimmune, inflammatory, and neurodegenerative diseases, aswell as ischemia-reperfusion injury and cancer. For example, activationof the alternative pathway of the complement cascade contributes to theproduction of C3a and C5a, both potent anaphylatoxins, which also haveroles in a number of inflammatory disorders. Therefore, in someinstances, it is desirable to decrease the response of the complementpathway, including the alternative complement pathway. Some examples ofdisorders mediated by the complement pathway include age-related maculardegeneration (AMD), paroxysmal nocturnal hemoglobinuria (PNH), multiplesclerosis, and rheumatoid arthritis.

Age-related macular degeneration (AMD) is a leading cause of vision lossin industrialized countries. Based on a number of genetic studies, thereis evidence of the link between the complement cascade and maculardegeneration. Individuals with mutations in the gene encoding complementFactor H have a fivefold increased risk of macular degeneration andindividuals with mutations in other complement factor genes also have anincreased risk of AMD. Individuals with mutant Factor H also haveincreased levels of C-reactive protein, a marker of inflammation.Without adequate functioning Factor H, the alternative pathway of thecomplement cascade is overly activated leading to cellular damage.Inhibition of the alternative pathway is thus desired.

Paroxysmal nocturnal hemoglobinuria (PNH) is a non-malignant,hematological disorder characterized by the expansion of hematopoieticstem cells and progeny mature blood cells which are deficient in somesurface proteins. PNH erythrocytes are not capable of modulating theirsurface complement activation, which leads to the typical hallmark ofPNH—the chronic activation of complement mediated intravascular anemia.Currently, only one product, the anti-C5 monoclonal antibody eculizumab,has been approved in the U.S. for treatment of PNH. However, many of thepatients treated with eculizumab remain anemic, and many patientscontinue to require blood transfusions. In addition, treatment witheculizumab requires life-long intravenous injections. Thus, there is anunmet need to develop novel inhibitors of the complement pathway.

Other disorders that have been linked to the complement cascade includeatypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome(HUS), abdominal aortic aneurysm, hemodialysis complications, hemolyticanemia, or hemodialysis, neuromylitis (NMO), myasthenia gravis (MG),fatty liver, nonalcoholic steatohepatitis (NASH), liver inflammation,cirrhosis, liver failure, dermatomyocitis, and amyotrophic lateralsclerosis.

Factor D is an attractive target for inhibition or regulation of thecomplement cascade due to its early and essential role in thealternative complement pathway, and its potential role in signalamplification within the classical and lectin complement pathways.Inhibition of Factor D effectively interrupts the pathway and attenuatesthe formation of the membrane attack complex.

While initial attempts have been made to develop inhibitors of Factor D,there are currently no small molecule Factor D inhibitors in clinicaltrials. Examples of Factor D inhibitors or prolyl compounds aredescribed in the following disclosures.

Biocryst Pharmaceuticals U.S. Pat. No. 6,653,340 titled “Compoundsuseful in the complement, coagulat and kallikrein pathways and methodfor their preparation” describes fused bicyclic ring compounds that arepotent inhibitors of Factor D. Development of the Factor D inhibitorBCX1470 was discontinued due to lack of specificity and short half-lifeof the compound.

Novartis PCT patent publication WO2012/093101 titled “Indole compoundsor analogues thereof useful for the treatment of age-related maculardegeneration” describes certain Factor D inhibitors. Additional Factor Dinhibitors are described in Novartis PCT patent publicationsWO2014/002051, WO2014/002052, WO2014/002053, WO2014/002054,WO2014/002057, WO2014/002058, WO2014/002059, WO2014/005150, andWO2014/009833.

Bristol-Myers Squibb PCT patent publication WO2004/045518 titled “Openchain prolyl urea-related modulators of androgen receptor function”describes open chain prolyl urea and thiourea related compounds for thetreatment of androgen receptor-associated conditions, such asage-related diseases, for example, sarcopenia.

Japan Tobacco Inc. PCT patent publication WO1999/048492 titled “Amidederivatives and nociceptin antagonists” describes compounds with aproline-like core and aromatic substituents connected to the prolinecore through amide linkages useful for the treatment of pain.

Ferring B. V. and Yamanouchi Pharmaceutical Co. lTD. PCT patentpublication WO1993/020099 titled “CCK and/or gastrin receptor ligands”describes compounds with a proline-like core and heterocyclicsubstituents connected to the proline core through amide linkages forthe treatment of, for example, gastric disorders or pain.

Alexion Pharmaceuticals PCT patent publication WO1995/029697 titled“Methods and compositions for the treatment of glomerulonephritis andother inflammatory diseases” discloses antibodies directed to C5 of thecomplement pathway for the treatment of glomerulonephritis andinflammatory conditions involving pathologic activation of thecomplement system. Alexion Pharmaceutical's anti-C5 antibody eculizumab(Soliris®) is currently the only complement-specific antibody on themarket, and is the first and only approved treatment for paroxysmalnocturnal hemoglobinuria (PNH).

On Feb. 25, 2015, Achillion Pharmaceuticals filed PCT Patent ApplicationNo. PCT/US2015/017523 and U.S. patent application Ser. No. 14/631,090titled “Alkyne Compounds for Treatment of Complement MediatedDisorders”; PCT Patent Application No. PCT/US2015/017538 and U.S. patentapplication Ser. No. 14/631,233 titled “Amide Compounds for Treatment ofComplement Mediated Disorders”; PCT Patent Application No.PCT/US2015/017554 and U.S. patent application Ser. No. 14/631,312 titled“Amino Compounds for Treatment of Complement Mediated Disorders”; PCTPatent Application No. PCT/US2015/017583 and U.S. patent applicationSer. No. 14/631,440 titled “Carbamate, Ester, and Ketone Compounds forTreatment of Complement Mediated Disorders”; PCT Patent Application No.PCT/US2015/017593 and U.S. patent application Ser. No. 14/631,625 titled“Aryl, Heteroaryl, and Heterocyclic Compounds for Treatment ofComplement Mediated Disorders”; PCT Patent Application No.PCT/US2015/017597 and U.S. patent application Ser. No. 14/631,683 titled“Ether Compounds for Treatment of Complement Mediated Disorders”; PCTPatent Application No. PCT/US2015/017600 and U.S. patent applicationSer. No. 14/631,785 titled “Phosphonate Compounds for Treatment ofComplement Mediated Disorders”; and PCT Patent Application No.PCT/US2015/017609 and U.S. patent application Ser. No. 14/631,828 titled“Compounds for Treatment of Complement Mediated Disorders” and U.S.patent application Ser. No. 14/630,959 titled “Factor D InhibitorsUseful for Treating Infectious Disorders.”

Given the wide variety of medical disorders that are caused bydetrimental immune or inflammatory responses, new uses and compounds areneeded for medical treatment. In one aspect, new uses and compounds areneeded to mediate the complement pathway, and for example, which act asFactor D inhibitors for treatment of disorders in a host, including ahuman, associated with misregulation of the complement cascade, or withundesired result of the complement cascade performing its normalfunction.

SUMMARY

This invention includes an active compound of Formula I, Formula I′ orFormula I″ or a pharmaceutically acceptable salt or composition thereof,wherein at least one R¹² or R¹³ on the A group is an amino substituent,for example R³². In one embodiment, an active compound or its salt orcomposition, as described herein is used to treat a medical disorderwhich is an inflammatory or immune condition, a disorder mediated by thecomplement cascade (including a dysfunctional cascade), a disorder orabnormality of a cell that adversely affects the ability of the cell toengage in or respond to normal complement activity, or an undesiredcomplement-mediated response to a medical treatment, such as surgery orother medical procedure or a pharmaceutical or biopharmaceutical drugadministration, a blood transfusion, or other allogenic tissue or fluidadministration.

These compounds can be used to treat such condition in a host in needthereof, typically a human. The active compound may act as an inhibitorof the complement factor D cascade. In one embodiment, a method for thetreatment of such a disorder is provided that includes theadministration of an effective amount of a compound of Formula I,Formula I′ or Formula I″ or a pharmaceutically acceptable salt thereof,optionally in a pharmaceutically acceptable carrier, as described inmore detail below.

In one embodiment, the disorder is associated with the alternativecomplement cascade pathway. In yet another embodiment, the disorder isassociated with the complement classical pathway. In a furtherembodiment, the disorder is associated with the complement lectinpathway. Alternatively, the active compound or its salt or prodrug mayact through a different mechanism of action than the complement cascade,or in particular as a complement factor D inhibitor, to treat thedisorder described herein.

In one embodiment, a method for the treatment of paroxysmal nocturnalhemoglobinuria (PNH) is provided that includes the administration of aneffective amount of a compound to a host of Formula I, Formula I′ orFormula I″ or a pharmaceutically acceptable salt thereof, optionally ina pharmaceutically acceptable carrier. In another embodiment, a methodfor the treatment of wet or dry age-related macular degeneration (AMD)in a host is provided that includes the administration of an effectiveamount of a compound of Formula I, Formula I′ or Formula I″ or apharmaceutically acceptable salt thereof, optionally in apharmaceutically acceptable carrier. In another embodiment, a method forthe treatment of rheumatoid arthritis in a host is provided thatincludes the administration of an effective amount of a compound ofFormula I, Formula I′ or Formula I″ or a pharmaceutically acceptablesalt thereof, optionally in a pharmaceutically acceptable carrier. Inanother embodiment, a method for the treatment of multiple sclerosis ina host is provided that includes the administration of an effectiveamount of a compound of Formula I, Formula I′ or Formula I″ or apharmaceutically acceptable salt thereof, optionally in apharmaceutically acceptable carrier.

In other embodiments, an active compound or its salt or prodrug asdescribed herein can be used to treat fatty liver and conditionsstemming from fatty liver, nonalcoholic steatohepatitis (NASH), liverinflammation, cirrhosis, and liver failure, dermatomyocitis, oramyotrophic lateral sclerosis.

The active compound or its pharmaceutically acceptable salt, prodrug ora pharmaceutical composition thereof as disclosed herein is also usefulfor administration in combination or alternation with a secondpharmaceutical agent for use in ameliorating or reducing a side effectof the second pharmaceutical agent. For example, in one embodiment, theactive compound may be used in combination with an adoptive celltransfer therapy to reduce an inflammatory response associated with suchtherapy, for example, a cytokine mediated response such as cytokineresponse syndrome. In one embodiment, the adoptive cell transfer therapyis a chimeric antigen receptor T-Cell (CAR T) or a dendritic cell usedto treat a hematologic or solid tumor, for example, a B-cell relatedhematologic cancer. In one embodiment, the hematologic or solid tumor isacute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML),non-Hodgkin's lymphoma, chronic lymphocytic leukemia (CLL), pancreaticcancer, glioblastoma, or a cancer that expresses CD19. In oneembodiment, the associated inflammatory response is a cytokine mediatedresponse.

Another embodiment is provided that includes the administration of aneffective amount of an active compound or a pharmaceutically acceptablesalt thereof, optionally in a pharmaceutically acceptable carrier to ahost to treat an ocular, pulmonary, gastrointestinal, or other disorderthat can benefit from topical or local delivery.

Any of the compounds described herein (Formula I, Formula I′ or FormulaI″) can be administered to the eye in any desired form ofadministration, including via intravitreal, intrastromal, intracameral,sub-tenon, sub-retinal, retro-bulbar, peribulbar, suprachorodial,choroidal, subchoroidal, conjunctival, subconjunctival, episcleral,posterior juxtascleralscleral, circumcorneal, and tear duct injections,or through a mucus, mucin, or a mucosal barrier, in an immediate orcontrolled release fashion.

In other embodiments of the invention, an active compound providedherein can be used to treat or prevent a disorder in a host mediated bycomplement factor D, or by an excessive or detrimental amount of thecomplement-C3 amplification loop of the complement pathway. As examples,the invention includes methods to treat or prevent complement associateddisorders that are induced by antibody-antigen interactions, a componentof an immune or autoimmune disorder or by ischemic injury. The inventionalso provides methods to decrease inflammation or an immune response,including an autoimmune response, where mediated or affected by factorD.

In another embodiment, a method is provided for treating a host,typically a human, with a disorder mediated by the complement system,that includes administration of a prophylactic antibiotic or vaccine toreduce the possibility of a bacterial infection during the treatmentusing one of the compounds described herein. In certain embodiments, thehost, typically a human, is given a prophylactic vaccine prior to,during or after treatment with one of the compounds described herein. Incertain embodiments, the host, typically a human, is given aprophylactic antibiotic prior to, during or after treatment with one ofthe compounds described herein. In some embodiment, the infection is ameningococcal infection (e.g., septicemia and/or meningitis), anAspergillus infection, or an infection due to an encapsulated organism,for example, Streptococcus pneumoniae or Haemophilus influenza type b(Hib), especially in children. In other embodiments, the vaccine orantibiotic is administered to the patient after contracting an infectiondue to, or concommitent with inhibition of the complement system.

The disclosure provides a compound of Formula I:

or a pharmaceutically acceptable composition, salt, isotopic analog, orprodrug thereof.

-   -   A is selected from A1, A1′ and A2.    -   B is selected from B1, B1′, B2, B3, and B4.    -   C is selected from C1, C1′, C2, C3, and C4.    -   L is selected from L1, L1′, L2, and L2′.    -   L3 is selected from L4 and L5.    -   At least one of A, B, C, L, or L3 is selected from A2, B3, C3,        L2, L2′, or L5.    -   Or at least one of A, B, C, L, or L3 is selected from A2, B3,        C4, L2, L2′, or L5    -   If C is C1, C1′ or C2, then Formula I includes at least one of        A2, B3, L2, L2′ or L5.    -   If C is C3, then Formula I can be any of A, B, L or L3.

C1 is

Q¹ is N(R¹) or C(R¹R¹).

Q² is C(R²R^(2′)), C(R²R^(2′))—C(R²R^(2′)), S, O, N(R²) or C(R²R^(2′)).

Q³ is N(R³), S, or C(R³R^(3′)).

X¹ and X² are independently N, CH, or CZ, or X¹ and X² together are C═C.

Q¹, Q², Q³, X¹, and X² are selected such that a stable compound results.

Z is F, Cl, NH₂, CH₃, CH₂D, CHD₂, or CD₃.

R¹, R^(1′), R², R^(2′), R³, and R^(3′) are independently selected ateach occurrence, as appropriate, and only where a stable compoundresults, from hydrogen, halogen, hydroxyl, nitro, cyano, amino,C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₂-C₆alkynyl,C₂-C₆alkanoyl, C₁-C₆thioalkyl, hydroxyC₁-C₆alkyl, aminoC₁-C₆alkyl,—C₀-C₄alkylNR⁹R¹⁰, —C(O)OR⁹, —OC(O)R⁹, —NR⁹C(O)R¹⁰, —C(O)NR⁹R¹⁰,—OC(O)NR⁹R¹⁰, —NR⁹C(O)OR¹⁰, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

R⁹ and R¹⁰ are independently selected at each occurrence from hydrogen,C₁-C₆alkyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl),and —O—C₀-C₄alkyl(C₃-C₇cycloalkyl).

In alternative embodiments, R¹ and R^(1′) or R³ and R^(3′) may be takentogether to form a 3- to 6-membered carbocyclic spiro ring or a 3- to6-membered heterocyclic spiro ring containing 1 or 2 heteroatomsindependently selected from N, O, or S; R² and R^(2′) may be takentogether to form a 3- to 6-membered carbocyclic spiro ring; or R² andR^(2′) may be taken together to form a 3- to 6-membered heterocyclicspiro ring; each of which spiro ring each of which ring may beunsubstituted or substituted with 1 or more substituents independentlyselected from halogen (and in particular F), hydroxyl, cyano, —COOH,C₁-C₄alkyl (including in particular methyl), C₂-C₄alkenyl, C₂-C₄alkynyl,C₁-C₄alkoxy, C₂-C₄alkanoyl, hydroxyC₁-C₄alkyl, (mono- anddi-C₁-C₄alkylamino)C₀-C₄alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl),—O—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

In alternative embodiments, R¹ and R² may be taken together to form a3-membered carbocyclic ring; R¹ and R² may be taken together to form a4- to 6-membered carbocyclic or aryl ring or a 4- to 6-memberedheterocyclic or heteroaryl ring containing 1 or 2 heteroatomsindependently selected from N, O, and S; or R² and R³, if bound toadjacent carbon atoms, may be taken together to form a 3- to 6-memberedcarbocyclic or aryl ring or a 3- to 6-membered heterocyclic orheteroaryl ring; each of which ring may be unsubstituted or substitutedwith 1 or more substituents independently selected from halogen (and inparticular F), hydroxyl, cyano, —COOH, C₁-C₄alkyl (including inparticular methyl), C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, hydroxyC₁-C₄alkyl, (mono- anddi-C₁-C₄alkylamino)C₀-C₄alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl),—O—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

In alternative embodiments, R¹ and R^(1′), R² and R^(2′), or R³ andR^(3′) can be taken together to form a carbonyl group. In alternativeembodiments, R¹ and R² or R² and R³ can be taken together to form acarbon-carbon double bond.

Any of the structures illustrated herein, e.g., A1, A1′, A2, B1, B1′,B2, B3, B4, C1, C1′, C2, C3, C4, L1, L1′, L2, L2′, L4 or L5 can beoptionally substituted with 0, 1, 2, 3, or 4, as appropriate, andindependently, of an R⁴⁸ substituent.

Non-limiting examples of C1 include the structures of FIG. 1 , wherein Rand R′ (see FIG. 5 ) are independently selected from H, alkyl,cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl wherein each group can beoptionally substituted or any other substituent group herein thatprovides the desired properties. In some embodiments, the ring includesone or more chiral carbon atoms. The invention includes embodiments inwhich the chiral carbon can be provided as an enantiomer, or mixtures ofenantiomers, including a racemic mixture. Where the ring includes morethan one stereocenter, all of the enantiomers and diastereomers areincluded in the invention as individual species, unless steoechemistryis specified.

In one embodiment, C1 is C1′.

Non-limiting examples of C1′ include the structures of FIG. 2 .

In one embodiment, a methyl group in a structure illustrated in FIG. 2can be replaced with a different alkyl group, as defined herein. Inanother embodiment, the fluoro atoms in the structures illustrated inFIG. 2 can be replaced with any other halogen. As indicated above, anyof the structures illustrated in FIG. 2 or otherwise can be optionallysubstituted with 0, 1, 2, 3, or 4, as appropriate, and independently,with an R⁴ substituent.

C2 is selected from:

wherein q is 0, 1, 2 or 3 and r is 1, 2 or 3.

R⁴⁴, R^(44′), R⁴⁵, R^(45′) are independently hydrogen, hydroxyl, amino,cyano, halogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle,heterocycloalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl;wherein each group can be optionally substituted, and such that a stableC2 results.

In one embodiment, R⁴⁴ and R^(44′), R⁴⁵ and R^(45′) or two R⁴⁷ groupscan be taken together to form a carbonyl group.

In an alternate embodiment, R⁴⁴ and R^(44′) or R⁴⁵ and R^(45′) or R⁴⁶and R^(46′) can be taken together to form an optionally substituted 3-to 6-membered carbocyclic spiro ring or a 3- to 6-membered heterocyclicspiro ring containing 1 or 2 heteroatoms independently selected from N,O, or S.

In one embodiment, R⁴⁴ and R⁴⁵ or R^(44′) and R^(45′) can be takentogether to form a 4- to 6-membered carbocyclic or aryl ring or a 4- to6-membered heterocyclic or heteroaryl ring; each of which ring may beunsubstituted or substituted with 1 or more substituents.

Non-limiting examples of C2 include the structures of FIG. 3 .

C3 is selected from:

X³ is C(R¹R^(1′)).

X⁴ is N or CH.

X^(4a) is N, CH or CZ.

X⁵ and X⁶ are C(R¹R^(1′)).

In alternative embodiments, X⁴ and X⁵ or X⁵ and X⁶ together are C═C.

X⁷ is SO or SO₂.

X⁸ is C(R¹R^(1′)) or N(R⁴³).

X^(5a) is C(R¹R^(1′)) or O.

Q⁴ is N or CH.

Q⁵ is N(R⁴⁷) or C(R⁴⁶R^(46′)).

Q^(5a) is C(R⁴⁷R⁴⁷), N(R⁴⁷), O, S, SO, or SO₂.

Q⁶ is N(R⁴⁷), C(R⁴⁶R^(46′)), S, or O.

Q⁷ is C(R⁴⁶R^(46′)), S or N(R⁴⁷).

Q⁸, Q⁹, Q¹⁰, Q¹¹ and Q¹² are each independently C(R²R^(2′)), S, SO, SO₂,O, N(R²), B(R⁵⁰), Si(R⁴⁹)₂, however if X¹ is N and X² is CH then L and Btaken together cannot be anisole substituted in the 4 position.

In a typical embodiment, no more than one heteroatom is in a three orfour membered C3 and no more than one, two or three heteroatoms can bein a five, six or seven membered C3. It is in general known by those ofskill in the art which combinations of several heteroatoms will not forma stable ring system. For example, those of skill in the art wouldunderstand that the C3 ring system would not normally contain an —O—O—,—O—S—, —Si—Si—, —B—B—, —B—Si—, bond.

R⁴⁰ is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl whereineach group can be optionally substituted.

R⁴² is halo, hydroxy, C₁-C₆alkoxy, C₁-C₆haloalkoxy, —SH, or—S(C₁-C₆alkyl).

R⁴³ is hydrogen, acyl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl whereineach group can be optionally substituted.

R⁴⁶ and R^(46′) are independently hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl,heteroaryl, or heteroarylalkyl wherein each group can be optionallysubstituted and at least one of R⁴⁶ or R^(46′) is not hydrogen.

R⁴⁷ is hydrogen, acyl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle,heterocycloalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkylwherein each group can be optionally substituted.

R⁴⁹ is halo, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle,heterocycloalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkylwherein each group can be optionally substituted or two R⁴⁹ groups canbe taken together to form a double bond that can be optionallysubstituted.

R⁵⁰ is hydroxy or C₁-C₆alkyoxy.

In one embodiment, the bridged heterocyclic C3 compounds can beoptionally substituted.

In one embodiment, X¹ and Q⁸ or Q⁸ and Q⁹ or Q⁹ and Q¹⁰ or Q¹⁰ and Q¹¹or Q¹¹ and Q¹² or Q¹² and X² can form a carbon-carbon double bond.

In one embodiment, two Q^(5a) groups or a X^(4a) and a Q^(5a) group canform a carbon-carbon double bond.

All of the variables presented herein, including but not limited to X¹,X², X³, X⁴, X⁵, X^(5a), X⁶, X⁷, X⁸, Q¹, Q², Q³, Q⁴, Q⁵, Q⁶, Q⁷, Q⁸, Q⁹,Q¹⁰, Q¹¹, Q¹², R¹, R⁴⁰, R⁴², R⁴³, R⁴⁴, R^(44′), R⁴⁵, and R^(45′) areindependently selected at each occurrence, as appropriate, and onlywhere a stable compound results. For example, when C3 is a 7-memberedring and comprises silicon or boron, the ring will only comprise oneSi(R⁴⁹)₂ or B(R⁵⁰) moiety. In addition, 3, 4, 5, 6 and 7-membered ringswill not comprise —O—O— or —O—S— bonds.

Non-limiting examples of C3 include the structures of FIG. 4 .

In one embodiment, the methyl groups in the structures illustrated inFIG. 4 can be replaced with a different alkyl group, as defined herein.In another embodiment, the fluoro atoms in the structures illustrated inFIG. 4 can be replaced with another halo. In another embodiment, halocan be chloro. As indicated above, any of the structures in FIG. 4 orherein can be optionally substituted with 0, 1, 2, 3, or 4, asappropriate, and independently, with an R⁴ substituent.

In an alternate embodiment, the central core moiety, C3, can comprise asmall mimetic of a beta-turn such as a benzodiazepine, a Friedingerlactam, a 2-oxo-1,3-oxazolidine-4-caroxylate or a β-D-glucose scaffold.See, De Marco, R. et al., “In-peptide synthesis of di-oxazolidinone anddehydroamino acid-oxazolidinone motifs as β-turn inducers”, J. Org.Biomol. Chem., 2013, 11, 4316-4326, Hirschmann, R. F. et al., Theβ-D-Glucose Scaffold as a β-Turn Mimetic, Accounts Chem. Res., 2009, 42,1511-1520 and Smith, A. B, et al., Accounts of Chem. Res., 2011, 44,180-193. In another embodiment, the central core moiety, C, can comprisea reverse turn mimetic that can include, but is not limited to; anon-peptidic residue, a metal chelation based mimic, or a foldamer. See,Nair, R. V. et al., “Synthetic turn mimetics and hairpin nucleators: QuoVadimus?”, Chem. Comm., 2014, 50, 13874-13884. In some embodiments, thecentral core moiety, C, can comprise a conformationally constrainedcyclic amino acid including but not limited to a (S)- or(R)-α-trifluoromethyl pyroglutamic acid derivative. See, Chaume, G. etal., “Concise access to enantiopure (S)- or (R)-α-trifluoromethylpyroglutamic acids from ethyl trifluoropyruvate-base chiralCF3-oxazolidines (Fox)”, J. Fluor. Chem., 2008, 129, 1104-1109 andAndre, C. et al., “(S)-ABOC: A Rigid Bicyclic β-Amino Acid as TurnInducer”, Org. Lett., 2012, 14, 960-963. In some embodiments, thecentral core moiety, C, can comprise a monomeric unit of a foldamer suchas, but not limited to an oxazolidin-2-one. See, Tomasii, C., AngelicimG. and Castellucci, N., “Foldamers Based on Oxazolidin-2-ones”, Eur. J.Org. Chem., 2011, 3648-3669.

Examples of central core small mimetics of a beta-turn, beta turninducers, reverse turn mimetics and foldamer monomers include, but arenot limited to those in FIG. 5 .

C4 is selected from

R¹⁰¹ is C₁-C₄ alkyl or C₃-C₇ cycloalkyl.

R² is C₁-C₄ alkyl, fluorine, chlorine, or bromine.

Non-limiting examples of C4 include

A1 is selected from:

Non-limiting examples of A1 include:

In one embodiment, A1 is A1′.

Non-limiting examples of A1′ include the structures of FIG. 6 .

A2 is selected from:

Non-limiting examples of A2 include the structures of FIG. 7 .

In one embodiment, additional examples include compounds wherein the2-methyl pyrimidine is replaced with a R³² moiety.

R⁴ is selected from -JCHO, -JCONH₂, JC₂-C₆alkanoyl, hydrogen, -JSO₂NH₂,-JC(CH₂)₂F, -JCH(CF₃)NH₂, C₁-C₆alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl),-JC(O)C₀-C₂alkyl(C₃-C₇cycloalkyl), JNR⁹(C₂-C₆alkanoyl), JNR⁹C(O)NR⁹R¹⁰,

each of which R⁴ other than hydrogen, or —CHO, is unsubstituted orsubstituted with one or more of amino, imino, halogen, hydroxyl, cyano,cyanoimino, C₁-C₂alkyl, C₁-C₂alkoxy, —C₀-C₂alkyl(mono- anddi-C₁-C₄alkylamino), C₁-C₂haloalkyl, and C₀-C₂haloalkoxy.

R^(4′) is selected from -JCHO, -JCONH₂, JC₂-C₆alkanoyl, hydrogen,-JSO₂NH₂, -JC(CH₂)₂F, -JCH(CF₃)NH₂, C₁-C₂alkyl,—C₀-C₄alkyl(C₃-C₇cycloalkyl), -JC(O)C₀-C₂alkyl(C₃-C₇cycloalkyl),JNR⁹(C₂-C₆alkanoyl),

each of which R^(4′) other than —CHO, is unsubstituted or substitutedwith one or more of amino, imino, halogen, hydroxyl, cyano, cyanoimino,C₁-C₂alkyl, C₁-C₂alkoxy, —C₀-C₂alkyl(mono- and di-C₁-C₄alkylamino),C₁-C₂haloalkyl, and C₀-C₂haloalkoxy.

R⁵ and R⁶ are independently selected from —CHO, —C(O)NH₂, —C(O)NH(CH₃),C₂-C₆alkanoyl, hydrogen, hydroxyl, halogen, cyano, nitro, —COOH,—SO₂NH₂, vinyl, C₁-C₆alkyl (including methyl), C₂-C₆alkenyl,C₁-C₆alkoxy, —C₀-C₄alkyl(C₃-C₇cycloalkyl),—C(O)C₀-C₄alkyl(C₃-C₇cycloalkyl), —P(O)(OR⁹)₂, —OC(O)R⁹, —C(O)OR⁹,—C(O)N(CH₂CH₂R⁹)(R¹⁰), —NR⁹C(O)R¹, phenyl, or 5- to 6-memberedheteroaryl. In one embodiment, R⁵ and R⁶ are each independently—C₀-C₄alkyl(C₃-C₇heterocycloalkyl), SO₂(C₁-C₆alkyl),SO₂(C₁-C₆haloalkyl), SO₂NR⁷R⁷, SO═NH(C₁-C₆alkyl),

-J-C₂-C₆alkanoyl, -J-C(O)NH₂, -J-SO₂NH₂, —C(O)NH(CH₃), -J-COOH,-J-C(O)C₀-C₄alkyl(C₃-C₇cycloalkyl), -J-P(O)(OR⁹)₂, -J-OC(O)R⁹,-J-C(O)OR⁹, -J-C(O)N(CH₂CH₂R⁹)(R¹⁰), -J-NR⁹C(O)R¹⁰, -J-phenyl, or -J-(5-to 6-membered heteroaryl) that can be optionally substituted.

Each R⁵ and R⁶ other than hydrogen, hydroxyl, cyano, and —COOH isunsubstituted or optionally substituted. For example, R⁵ and R⁶ otherthan hydrogen, hydroxyl, cyano, and —COOH may be substituted with one ormore substituents independently selected from halogen, hydroxyl, amino,imino, cyano, cyanoimino, C₁-C₂alkyl, C₁-C₄alkoxy, —C₀-C₂alkyl(mono- anddi-C₁-C₄alkylamino), C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

R^(6′) is hydrogen, halogen, hydroxyl, C₁-C₄alkyl,—C₀-C₄alkyl(C₃-C₇cycloalkyl), or C₁-C₄alkoxy; or R⁶ and R^(6′) may betaken together to form an oxo, vinyl, or imino group.

R⁷ is hydrogen, C₁-C₆alkyl, or —C₀-C₄alkyl(C₃-C₇cycloalkyl).

R⁸ and R^(8′) are independently selected from hydrogen, halogen,hydroxyl, C₁-C₆alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₆alkoxy, and(C₁-C₄alkylamino)C₀-C₂alkyl; or R⁸ and R^(8′) are taken together to forman oxo group; or R⁸ and R^(8′) can be taken together with the carbonthat they are bonded to form a 3-membered carbocyclic ring.

R¹⁶ is absent or is independently selected from halogen, hydroxyl,nitro, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkanoyl, C₁-C₆alkoxy,—C₀-C₄alkyl(mono- and di-C₁-C₆alkylamino), —C₀-C₄alkyl(C₃-C₇cycloalkyl),C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

R¹⁹ is hydrogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkanoyl,—SO₂C₁-C₆alkyl, (mono- and di-C₁-C₆alkylamino)C₁-C₄alkyl,—C₀-C₄alkyl(C₃-C₇cycloalkyl), —C₀-C₄alkyl(C₃-C₇heterocycloalkyl),—C₀-C₄alkyl(aryl), C₀-C₄alkyl(heteroaryl), and wherein R¹⁹ other thanhydrogen is unsubstituted or substituted with one or more substituentsindependently selected from halogen, hydroxyl, amino, —COOH, and—C(O)OC₁-C₄alkyl.

X¹¹ is N or CR¹¹.

X¹² is N or CR¹².

X¹³ is N or CR¹³.

X¹⁴ is N or CR¹⁴.

No more than 2 of X¹¹, X¹², X¹³, and X¹⁴ are N.

One of R¹² and R¹³ is selected from R³¹ and the other of R¹² and R¹³ isselected from R³², however, each compound has at least one R³². In analternative embodiment, R¹² and R¹³ are each independently selected froman R³² moiety.

R³¹ is selected from hydrogen, halogen, hydroxyl, nitro, cyano, amino,—COOH, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₆alkyl,—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₂-C₆alkenyl, C₂-C₆alkanoyl, C₁-C₆alkoxy,C₂-C₆alkenyloxy, —C(O)OR⁹, C₁-C₆thioalkyl, —C₀-C₄alkylNR⁹R¹⁰,—C(O)NR⁹R¹⁰, —SO₂R⁹, —SO₂NR⁹R¹⁰, —OC(O)R⁹, and —C(NR⁹)NR⁹R¹⁰, each ofwhich R³¹ other than hydrogen, halogen, hydroxyl, nitro, cyano,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy is unsubstituted or substituted withone or more substituents independently selected from halogen, hydroxyl,nitro, cyano, amino, —COOH, —CONH₂ C₁-C₂haloalkyl, and C₁-C₂haloalkoxy,and each of which R³¹ is also optionally substituted with onesubstituent selected from phenyl and 4- to 7-membered heterocyclecontaining 1, 2, or 3 heteroatoms independently selected from N, O, andS; which phenyl or 4- to 7-membered heterocycle is unsubstituted orsubstituted with one or more substituents independently selected fromhalogen, hydroxyl, nitro, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkanoyl, C₁-C₆alkoxy, (mono- and di-C₁-C₆alkylamino)C₀-C₄alkyl,C₁-C₆alkylester, —C₀-C₄alkyl)(C₃-C₇cycloalkyl), C₁-C₂haloalkyl, andC₁-C₂haloalkoxy.

R³² is selected from NR⁷²R⁷³, NR⁹SO₂R⁷³, N(SO₂R⁹)CH₂C(O)R⁷⁴.

R¹¹, R¹⁴, and R¹⁵ are independently selected at each occurrence fromhydrogen, halogen, hydroxyl, nitro, cyano, —O(PO)(OR⁹)₂, —(PO)(OR⁹)₂,C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₂-C₆alkenyl(aryl),C₂-C₆alkenyl(cycloalkyl), C₂-C₆alkenyl(heterocycle),C₂-C₆alkenyl(heteroaryl), C₂-C₆alkynyl, C₂-C₆alkynyl(aryl),C₂-C₆alkynyl(cycloalkyl), C₂-C₆alkynyl(heterocycle),C₂-C₆alkynyl(heteroaryl), C₂-C₆alkanoyl, C₁-C₆alkoxy, C₁-C₆thioalkyl,—C₀-C₄alkyl(mono- and di-C₁-C₆alkylamino), —C₀-C₄alkyl(C₃-C₇cycloalkyl),—C₀-C₄alkoxy(C₃-C₇cycloalkyl), C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

X¹⁵ is NH, O, or S.

X¹⁶ is CR¹².

X¹⁷ is N or CR¹³.

X¹¹ is CR¹².

X¹⁹ is N or CR¹³.

X²⁰ is NH or O.

X²¹ is N or CR¹⁴.

X²² is N or CR¹³.

X²³ is CR¹².

X²⁴ and X²⁵ are each independently O or S.

X²⁶ is N or CR⁴¹.

X²⁷ is CR¹², NH or O.

X²⁸ is N or CH.

X³⁰ is N or CR⁵.

X³¹ is N, C(R⁵⁴)₂ or CR⁵⁴.

X³² is NH, C(R⁵⁴)₂ or CR⁵⁴.

X³³ is —CO— or —SO— or —SO₂—.

X³⁴ is CHR¹³, NH, O, or S.

No more than 2 of X²⁸ are N.

R³⁰ is independently selected at each occurrence from hydrogen,C₁-C₆alkyl, C₁-C₆haloalkyl, (aryl)C₀-C₄alkyl,(C₃-C₇cycloalkyl)C₀-C₄alkyl, (phenyl)C₀-C₄alkyl, (4- to 7-memberedheterocycloalkyl)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S; (5- or 6-membered unsaturated or aromaticheterocycle)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S; COOH, Si(CH₃)₃, COOR^(30a), C₂-C₆alkanoyl,—B(OH)₂, —C(O)(CH₂)₁₋₄S(O)R²¹, —P(O)(OR²¹)(OR²²), —P(O)(OR²¹)R²²,—P(O)R²¹R²², —NR⁹P(O)(NHR²¹)(NHR²²), —NR⁹P(O)(OR²¹)(NHR²²),—NR⁹P(O)(OR²¹)(OR²²), —C(S)R²¹, —NR²¹SO₂R²², —NR⁹S(O)NR¹⁰R²²,—NR⁹SO₂NR¹⁰R²², —SO₂NR⁹COR²², —SO₂NR⁹CONR²¹R²², —NR²¹SO₂R²²,—C(O)NR²¹SO₂R²², —C(NH₂)NR⁹R²², —C(NH₂)NR⁹S(O)₂R²², —NR⁹C(O)OR¹⁰,—NR²¹OC(O)R²², —(CH₂)₁₋₄C(O)NR²¹R²², —C(O)R²⁴R²⁵, —NR⁹C(O)R²¹, —C(O)R²¹,—NR⁹C(O)NR⁹R¹⁰, —NR⁹C(O)NR²⁴R²⁵, —(CH₂)₁₋₄OC(O)R²¹, each of which R³⁰can be optionally substituted.

R⁴¹ is hydrogen, C₁-C₆alkyl, or —(C₀-C₂alkyl)(C₃-C₅cycloalkyl).

R⁴⁸ is independently selected from hydrogen, halogen, hydroxyl, nitro,cyano, amino, C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆thioalkyl, C₁-C₆alkoxy, -JC₃-C₇cycloalkyl, —B(OH)₂, -JC(O)NR⁹R²³,-JOSO₂OR²¹, —C(O)(CH₂)₁₋₄S(O)R²¹, —O(CH₂)₁₋₄S(O)NR²¹R²²,-JOP(O)(OR²¹)(OR²²), -JP(O)(OR²¹)(OR²²), -JOP(O)(OR²¹)R²²,-JP(O)(OR²¹)R²², -JOP(O)R²¹R²², -JP(O)R²¹R²², -JSP(O)(OR²¹)(OR²²),-JSP(O)(OR²¹)(R²²), -JSP(O)(R²¹)(R²²), -JNR⁹P(O)(NHR²¹)(NHR²²)-JNR⁹P(O)(OR²¹)(NHR²²) -JNR⁹P(O)(OR²¹)(OR²²), -JC(S)R²¹, -JNR²¹SO₂R²²,-JNR⁹S(O)NR¹⁰R²², -JNR⁹SO₂NR¹⁰R²², -JSO₂NR⁹COR²², -JSO₂NR⁹CONR²¹R²²,-JNR²¹SO₂R²², -JC(O)NR²¹SO₂R²², -JC(NH₂)═NR²², -JCH(NH₂)NR⁹S(O)₂R²²,-JOC(O)NR²¹R²², -JNR²¹C(O)OR²², -JNR²¹OC(O)R²², —(CH₂)₁₋₄C(O)NR²¹R²²,-JC(O)NR²⁴R²⁵, -JNR⁹C(O)R²¹, -JC(O)R²¹, -JNR⁹C(O)NR¹⁰R²², —CCR²¹,—(CH₂)₁₋₄OC(O)R²¹, -JC(O)OR²³; each of which R⁴⁸ may be unsubstituted orsubstituted with one or more substituents independently selected fromhalogen, hydroxyl, nitro, cyano, amino, oxo, —B(OH)₂, —Si(CH₃)₃, —COOH,—CONH₂, —P(O)(OH)₂, C₁-C₆alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl),C₁-C₆alkoxy, —C₀-C₄alkyl(mono- and di-C₁-C₄alkylNR⁹R¹⁰),C₁-C₆alkylester, C₁-C₄alkylamino, C₁-C₄hydroxylalkyl, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, —OC(O)R⁹, —NR⁹C(O)R¹⁰, —C(O)NR⁹R¹⁰, —OC(O)NR⁹R¹⁰,—NR⁹C(O)OR¹⁰, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

R^(48a) is R⁴⁸, S(O)═NHR²¹, SF₅, and JC(R⁹)═NR²¹ and SO₂OR²¹.

R⁵⁴ is hydrogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy,C₂-C₆alkynyl, C₂-C₆alkanoyl, C₁-C₆thioalkyl, hydroxyC₁-C₆alkyl,aminoC₁-C₆alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl), (phenyl)C₀-C₄alkyl-,(heterocycloalkyl)C₀-C₄alkyl and (heteroaryl)C₀-C₄alkyl- wherein thegroups can be optionally substituted.

R⁷² is selected at each occurrence from aryl, heteroaryl, heterocycle,alkynyl, hydroxyl, C₁-C₆alkoxy, (C₃-C₇cycloalkyl)C₀-C₄alkyl,(aryl)C₀-C₄alkyl, (heterocycle)C₀-C₄alkyl, (heteroaryl)C₀-C₄alkyl,—C₁-C₄alkylOC(O)OC₁-C₆alkyl, —C₁-C₄alkylOC(O)C₁-C₆alkyl,—C₁-C₄alkylC(O)OC₁-C₆alkyl, —S(O)(O)(alkyl), —S(O)(alkyl),—S(O)(O)(heteroalkyl), —S(O)(heteroalkyl), —S(O)(O)(aryl), —S(O)(aryl),—S(O)(O)(heteroaryl), —S(O)(heteroaryl), (and in some embodiments is a(4- to 7-membered heterocycloalkyl)C₀-C₄alkyl having 1, 2, or 3heteroatoms independently selected from N, O, and S, and (5- or6-membered saturated or partially unsaturated heterocycle)C₀-C₄alkylhaving 1, 2, or 3 heteroatoms independently selected from N, O, and S),each of which groups can be optionally substituted.

R⁷³ is selected at each occurrence from hydrogen, hydroxyl, cyano,amino, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,(C₃-C₇cycloalkyl)C₀-C₄alkyl, (phenyl)C₀-C₄alkyl,—C₁-C₄alkylOC(O)OC₁-C₆alkyl, —C₁-C₄alkylOC(O)C₁-C₆alkyl,—C₁-C₄alkylC(O)OC₁-C₆alkyl, (4- to 7-memberedheterocycloalkyl)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S, and (5- or 6-membered unsaturated or aromaticheterocycle)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S, each of which groups can be optionallysubstituted.

R⁷⁴ is an optionally substituted proline amide.

s is 1 or 2.

L is selected from L1, L1′, L2, L2′.

L1 is a bond or is selected from the formulas

R¹⁷ is hydrogen, C₁-C₆alkyl, or —C₀-C₄alkyl(C₃-C₇cycloalkyl) and R¹⁸ andR^(18′) are independently selected from hydrogen, halogen,hydroxymethyl, and methyl; and m is 0, 1, 2, or 3.

In one embodiment, L1 is L1′.

Non-limiting examples of L1′ include the structures of FIG. 8 .

In one embodiment, the methyl groups in the structures illustrated inFIG. 8 can be replaced with an alkyl group, as defined herein.

L2 is selected from:

Or an optionally substituted monocyclic or bicyclic carbocyclic; anoptionally substituted monocyclic or bicyclic carbocyclic-oxy group; anoptionally substituted monocyclic or bi-cyclic heterocyclic group having1, 2, 3, or 4 heteroatoms independently selected from N, O, and S andfrom 4 to 7 ring atoms per ring, an optionally substituted—(C₀-C₄alkyl)(aryl); an optionally substituted —(C₀-C₄alkyl)(5-memberedheteroaryl) selected from pyrrole, furan, thiophene, pyrazole, oxazole,isoxazole, thiazole and isothiazole or a substituted imidazole; anoptionally substituted —(C₀-C₄alkyl)(6-membered heteroaryl); anoptionally substituted —(C₀-C₄alkyl)(8-membered heteroaryl); anoptionally substituted —(C₀-C₄alkyl)(9-membered heteroaryl) selectedfrom isoindole, indazole, purine, indolizine, benzothiophene,benzothiazole, benzoxazole, benzofuran, and furopyridine; and—(C₀-C₄alkyl)(10-membered heteroaryl); q is 1, 2 or 3.

L2′ is selected from:

wherein R⁵¹ is CH₃, CH₂F, CHF₂ or CF₃.

wherein R⁵³ is cyano, nitro, hydroxyl or C₁-C₆alkoxy.

X²⁹ can be O or S.

In certain embodiment, L2 is a bond. In certain embodiments, if L2 isheterocyclic or heteroaryl, then B can be hydrogen.

Non-limiting examples of L2 include the structures of FIG. 9 .

In one embodiment, the methyl groups in the structures illustrated inFIG. 9 can be replaced with an alkyl or acyl, as defined herein Inanother embodiment, the carbocyclic, heterocyclic, aryl or heteroarylrings can be optionally substituted. As indicated above, any of thestructures illustrated in FIG. 9 or herein can be optionally substitutedwith 0, 1, 2, 3, or 4, as appropriate, and independently, of an R⁴⁸substituent.

L3 is selected from L4 or L5.

L4 is —C(O)—.

L5 is —C(S)—, —P(O)OH—, —S(O)—, —S(O)₂— or —C(R⁵²)₂— wherein each R⁵² isindependently selected from halo, hydrogen, or optionally substitutedC₁-C₆alkyl. In certain embodiments the two R⁵² groups can be takentogether to form a 3- to 6-membered carbocyclic spiro ring or a 3- to6-membered heterocyclic spiro ring containing 1 or 2 heteroatomsindependently selected from N, O, or S.

B1 is a monocyclic or bicyclic carbocyclic; a monocyclic or bicycliccarbocyclic-oxy group; a monocyclic, bicyclic, or tricyclic heterocyclicgroup having 1, 2, 3, or 4 heteroatoms independently selected from N, O,and S and from 4 to 7 ring atoms per ring; C₂-C₆alkenyl; C₂-C₆alkynyl;—(C₀-C₄alkyl)(aryl); —(C₀-C₄alkyl)(heteroaryl); or—(C₀-C₄alkyl)(biphenyl), each of which B1 is unsubstituted orsubstituted with one or more substituents independently selected fromR³³ and R³⁴, and 0 or 1 substituents selected from R³⁵ and R³⁶.

R³³ is independently selected from halogen, hydroxyl, —COOH, cyano,C₁-C₆alkyl, C₂-C₆alkanoyl, C₁-C₆alkoxy, —C₀-C₄alkylNR⁹R¹⁰, —SO₂R⁹,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

R³⁴ is independently selected from nitro, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆thioalkyl, -JC₃-C₇cycloalkyl, —B(OH)₂, -JC(O)NR⁹R²³, -JOSO₂OR²¹,—C(O)(CH₂)₁₋₄S(O)R²¹, —O(CH₂)₁₋₄S(O)NR²¹R²², -JOP(O)(OR²¹)(OR²²),-JP(O)(OR²¹)(OR²²), -JOP(O)(OR²¹)R²², -JP(O)(OR²¹)R²², -JOP(O)R²¹R²²,-JP(O)R²¹R²², -JSP(O)(OR²¹)(OR²²), -JSP(O)(OR²¹)(R²²),-JSP(O)(R²¹)(R²²), -JNR⁹P(O)(NHR²¹)(NHR²²), -JNR⁹P(O)(OR²¹)(NHR²²),-JNR⁹P(O)(OR²¹)(OR²²), -JC(S)R²¹, -JNR²¹SO₂R²², -JNR⁹S(O)NR¹⁰R²²,-JNR⁹SO₂NR¹⁰R²², -JSO₂NR⁹COR²², -JSO₂NR⁹CONR²¹R²², -JNR²¹SO₂R²²,-JC(O)NR²¹SO₂R²², -JC(NH₂)═NR²², -JCH(NH₂)NR⁹S(O)₂R²², -JOC(O)NR²¹R²²,-JNR²¹C(O)OR²², -JNR²¹OC(O)R²², —(CH₂)₁₋₄C(O)NR²¹R²², -JC(O)R²⁴R²⁵,-JNR⁹C(O)R²¹, -JC(O)R²¹, -JNR⁹C(O)NR¹⁰R²², —CCR²¹, —(CH₂)₁₋₄OC(O)R²¹,and -JC(O)OR²³; each of which R³⁴ may be unsubstituted or substitutedwith one or more substituents independently selected from halogen,hydroxyl, nitro, cyano, amino, oxo, —B(OH)₂, —Si(CH₃)₃, —COOH, —CONH₂,—P(O)(OH)₂, C₁-C₆alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₆alkoxy,—C₀-C₂alkyl(mono- and di-C₁-C₄alkylamino), C₁-C₆alkylester,C₁-C₄alkylamino, C₁-C₄hydroxylalkyl, C₁-C₂haloalkyl, andC₁-C₂haloalkoxy.

R³⁵ is independently selected from naphthyl, naphthyloxy, indanyl, (4-to 7-membered heterocycloalkyl)C₀-C₄alkyl containing 1 or 2 heteroatomsselected from N, O, and S, and bicyclic heterocycle containing 1, 2, or3 heteroatoms independently selected from N, O, and S, and containing 4-to 7-ring atoms in each ring; each of which R³⁵ is unsubstituted orsubstituted with one or more substituents independently selected fromhalogen, hydroxyl, nitro, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkanoyl, C₁-C₆alkoxy, (mono- and di-C₁-C₆alkylamino)C₀-C₄alkyl,C₁-C₆alkylester, —C₀-C₄alkyl(C₃-C₇cycloalkyl), —SO₂R⁹, C₁-C₂haloalkyl,and C₁-C₂haloalkoxy.

R³⁶ is independently selected from tetrazolyl, (phenyl)C₀-C₂alkyl,(phenyl)C₁-C₂alkoxy, phenoxy, and 5- or 6-membered heteroaryl containing1, 2, or 3 heteroatoms independently selected from N, O, B, and S, eachof which R³⁶ is unsubstituted or substituted with one or moresubstituents independently selected from halogen, hydroxyl, nitro,cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkanoyl, C₁-C₆alkoxy, (mono- anddi-C₁-C₆alkylamino)C₀-C₄alkyl, C₁-C₆alkylester,—C₀-C₄alkyl(C₃-C₇cycloalkyl), —SO₂R⁹, —OSi(CH₃)₂C(CH₃)₃,—Si(CH₃)₂C(CH₃)₃, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

In one additional alternative embodiment B is selected from:

In one additional alternative embodiment R³⁶ is selected from:

In one embodiment R¹ is selected from F, Cl, Br, and C₁-C₆alkyl.

In one embodiment R¹ is selected from hydroxyl and C₁-C₆alkoxy.

In one embodiment R¹ is selected from C₂-C₆alkynyl, C₂-C₆alkanoyl, andC₁-C₆thioalkyl.

In one embodiment R¹ is selected from aminoC₁-C₆alkyl and—C₀-C₄alkyNR⁹R¹⁰.

R²¹ and R²² are independently selected at each occurrence from hydrogen,hydroxyl, cyano, amino, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,(C₃-C₇cycloalkyl)C₀-C₄alkyl, (phenyl)C₀-C₄alkyl,—C₁-C₄alkylOC(O)OC₁-C₆alkyl, —C₁-C₄alkylOC(O)C₁-C₆alkyl,—C₁-C₄alkylC(O)OC₁-C₆alkyl, (4- to 7-memberedheterocycloalkyl)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S, and (5- or 6-membered unsaturated or aromaticheterocycle)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S, and each R²¹ and R²² can be optionallysubstituted. In one embodiment, R²¹ and R²² can be taken together toform a carbocyclic or heterocyclic ring.

R²³ is independently selected at each occurrence from C₁-C₆alkyl,C₁-C₆haloalkyl, (aryl)C₀-C₄alkyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl,(phenyl)C₀-C₄alkyl, (4- to 7-membered heterocycloalkyl)C₀-C₄alkyl having1, 2, or 3 heteroatoms independently selected from N, O, and S, and (5-or 6-membered unsaturated or aromatic heterocycle)C₀-C₄alkyl having 1,2, or 3 heteroatoms independently selected from N, O, and S, and eachR²³ can be optionally substituted.

R²⁴ and R²⁵ are taken together with the nitrogen to which they areattached to form a 4- to 7-membered monocyclic heterocycloalkyl group,or a 6- to 10-membered bi-cyclic heterocyclic group having fused, spiro,or bridged rings, and each R²⁴ and R²⁵ can be optionally substituted.

J is independently selected at each occurrence from a covalent bond,C₁-C₄alkylene, —OC₁-C₄alkylene, C₂-C₄alkenylene, and C₂-C₄alkynylene.

In one embodiment, B1 is selected from the structures of FIG. 10 ,wherein R²⁷ is hydrogen, methyl, or trifluoromethyl; R²⁸ is hydrogen orhalogen; and R²⁹ is hydrogen, methyl, trifluoromethyl, or—Si(CH₃)₂C(CH₃)₃.

In one embodiment, B1 is B1′. Non-limiting examples of B1′ include thestructures of FIGS. 11 A-D.

Examples of B moieties include, but are not limited to

In one embodiment, B is B2 which is selected from the structures of FIG.12 .

-   -   (I) In one embodiment B3 is:    -   (II) a monocyclic or bicyclic carbocyclic; a monocyclic or        bicyclic carbocyclic-oxy group; a monocyclic, bicyclic, or        tricyclic heterocyclic group having 1, 2, 3, or 4 heteroatoms        independently selected from N, O, and S and from 4 to 7 ring        atoms per ring; C₂-C₆alkenyl; C₂-C₆alkynyl; —(C₀-C₄alkyl)(aryl);        —(C₀-C₄alkyl)(heteroaryl); or —(C₀-C₄alkyl)(biphenyl); each of        which B3 is substituted with one or more of the following:        S(O)═NHR²¹, SF₅, and JC(R⁹)═NR²¹;    -   (III) a monocyclic, bicyclic, or tricyclic heterocyclic group        that has at least one boron or silicon atom in the ring or a        monocyclic, bicyclic, or tricyclic heteroaryl group that has at        least one boron in the ring;    -   (IV) a 6-membered aryl group fused to a 5-membered saturated        cyclic group that optionally contains 1 or 2 heteroatoms        independently selected from N and S wherein one of the CH2        groups of the 5-membered cyclic group is optionally substituted        by oxo (i.e., ═O) excluding dihydrobenzofuran;    -   (V) an 8-membered monocyclic or bicyclic heteroaryl, however;        when A is A1 or A1′; C is C1, C1′ or C2; L is L1 or L1′ and L3        is L4 the following species are excluded:        6,7-dihydro-5H-pyrrolo[1,2-a]imidazole.    -   (VI) a 9-membered monocyclic or bicyclic heteroaryl group,        however; when A is A1 or A1′; C is C1, C1′ or C2; L is L1 or L1′        and L3 is L4 the following species are excluded:        6-chloro-1H-benzo[d]imidazole bonded at the 7 position,        6-fluoro-1H-benzo[d]imidazole bonded at the 7 position,        6-(methylthio)-1H-benzo[d]imidazole bonded at the 7 position,        and 6-(methoxy)-1H-benzo[d]imidazole bonded at the 7 position,        7-chloro-imidazo[1,2-a]pyridine substituted at the eight        position, 7-(methylthio)-imidazo[1,2-a]pyridine substituted at        the eight position, 7-fluoro-imidazo[1,2-a]pyridine substituted        at the eight position, 7-methoxyimidazo[1,2-a]pyridine        substituted at the eight position, 4-fluoro-1H-indole        substituted at the 4 position, [1,2,4]triazole[4,3-a]pyridine        substituted at the 2 position, and        [1,2,4]triazole[4,3-a]pyrimidine substituted at the 3 position;    -   (VII) a 10-membered aryl or heteroaryl group, however; when A is        A1 or A1′; C is C1, C1′ or C2; L is L1 or L1′ and L3 is L4 the        following species are excluded: an unsubstituted        tetrahydroquinoline and        6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepine substituted        at the 3-position;    -   (VIII) (optionally substituted alkyl)-(optionally substituted        cycloalkyl), (optionally substituted alkenyl)-(optionally        substituted cycloalkyl), or (optionally substituted        alkynyl)-(optionally substituted cycloalkyl);

wherein B3 can be further substituted one or more times with thesubstituents independently selected from R³⁵, R³⁶ and R⁴⁸.

Non-limiting examples of B3 include the structures of FIG. 13 .

In one embodiment, the methyl groups in the structures illustrated inFIG. 13 can be replaced by another alkyl group. In another embodiment,the B3 groups illustrated in FIG. 13 can be optionally substituted. Asindicated above, any of the structures illustrated in FIG. 13 orotherwise herein can be optionally substituted with 0, 1, 2, 3, or 4, asappropriate, and independently, with an R⁴⁸ substituent.

In an alternative embodiment, B3 can also be R²¹ when L2 is either anoptionally substituted monocyclic or bicyclic carbocyclic; an optionallysubstituted monocyclic or bi-cyclic carbocyclic-oxy group; an optionallysubstituted monocyclic or bicyclic heterocyclic group having 1, 2, 3, or4 heteroatoms independently selected from N, O, and S and from 4 to 7ring atoms per ring, an optionally substituted —(C₀-C₄alkyl)(aryl); anoptionally substituted —(C₀-C₄alkyl)(5-membered heteroaryl) selectedfrom pyrrole, furan, thiophene, pyrazole, oxazole, isoxazole, thiazoleand isothiazole or a substituted imidazole; an optionally substituted—(C₀-C₄alkyl)(6-membered heteroaryl); an optionally substituted—(C₀-C₄alkyl)(8-membered heteroaryl); an optionally substituted—(C₀-C₄alkyl)(9-membered heteroaryl) selected from isoindole, indazole,purine, indolizine, benzothiophene, benzothiazole, benzoxazole,benzofuran, and furopyridine; or an optionally substituted—(C₀-C₄alkyl)(10-membered heteroaryl)

Non-limiting examples of L2-B3 where B3 is R²¹ include the structures ofFIG. 14 .

B4 is one of the following defined embodiments and is subject to therestriction that either A is A2, or C is C3 (or C4), or L is L2 or L2′,or L3 is L5:

-   -   (I) a 4-membered carbocyclic fused to a 5- or 6-membered        heteroaryl having 1, 2, or 3 heteroatoms independently selected        from N, O, and S; wherein the 4-5 or 4-6 ring system can be        optionally substituted;    -   (II) a 4-membered carbocyclic fused to a 6-membered aryl ring        wherein the 4-6 ring system can be optionally substituted;    -   (III) a monocyclic or bicyclic carbocyclic; a monocyclic or        bicyclic carbocyclic-oxy group; a monocyclic, bicyclic, or        tricyclic heterocyclic group having 1, 2, 3, or 4 heteroatoms        independently selected from N, O, and S and from 4 to 7 ring        atoms per ring; C₂-C₆alkenyl; C₂-C₆alkynyl; —(C₀-C₄alkyl)(aryl);        —(C₀-C₄alkyl)(heteroaryl); or —(C₀-C₄alkyl)(biphenyl); each of        which B3 is substituted one or more times with S(O)₂OR²¹;    -   (IV) (cycloalkyl)-(optionally substituted aryl),        (cycloalkyl)-(optionally substituted heteroaryl),        (cycloalkyl)-(optionally substituted heterocyclic),        (alkyl)-alkenyl), cycloalkyl-alkenyl;    -   (V) alkyl, (alkyl)-(alkenyl), alkyl(alkynyl), cycloalkyl-alkenyl        each of which can be optionally substituted;    -   (VI) (optionally substituted alkyl)-(optionally substituted        cycloalkyl), (alkenyl)-(optionally substituted cycloalkyl),        (alkynyl)-(optionally substituted cycloalkyl), (optionally        substituted cycloalkyl)-(optionally substituted cycloalkyl);

wherein B4 can be further substituted 1, 2, 3 or 4 times or more withthe substituents independently selected from R³³, R³⁴, R³⁵ R³⁶ and R⁴⁸.

In an alternate embodiment, the R³² group can be bonded to B via alinking group to form a compound of Formula I′:

wherein;

X⁹ is CH₂ or O and X¹⁰ is CH₂, NR⁹, O or S;

p is 2 to 10;

or a pharmaceutically acceptable composition, salt, isotopic analog, orprodrug thereof.

In one embodiment, the disclosure provides a compound of Formula IM.

In one embodiment, the disclosure provides a compound of Formula IN:

In one embodiment, the disclosure provides a compound of Formula IO:

In one embodiment, the disclosure provides a compound of Formula IP:

In one embodiment, the disclosure provides a compound of Formula IQ:

In one embodiment, the disclosure provides a compound of Formula IR:

In an alternate embodiment, the X⁹—(CH₂)_(p)—X¹⁰ moiety can be saturatedor partially unsaturated. In another embodiment, the X⁹—(CH₂)_(p)—X¹⁰moiety can comprise one or more heteroatoms.

In an alternate embodiment, the A group can be bonded to B via a linkinggroup to form a compound of Formula I′A:

wherein;

X^(9′) and X¹⁰ are each independently CH₂, NR⁹, O or S;

t is 1, 2, or 3;

or a pharmaceutically acceptable composition, salt, isotopic analog, orprodrug thereof.

In one embodiment, the disclosure provides a compound of Formula IS:

In one embodiment, the disclosure provides a compound of Formula IT:

In an alternate embodiment, the X^(9′)—(CH₂)_(t)—X¹⁰ moiety can besaturated or partially unsaturated. In another embodiment, theX^(9′)—(CH₂)_(t)—X¹⁰ moiety can comprise one or more heteroatoms.

In an alternate embodiment, the disclosure provides compounds of FormulaI″

or a pharmaceutically acceptable composition, salt, isotopic analog, orprodrug thereof.

-   -   A is selected from A1, A1′ and A2.    -   B is selected from B1, B1′, B2, B3, and B4.    -   L is selected from L1, L1′, L2, and L2′.    -   L3 is selected from L4 and L5.

R³⁷ is hydrogen, C₁-C₆alkyl or —(C₀-C₂alkyl)(C₃-C₆cycloalkyl).

R³⁸ and R³⁹ are independently hydrogen (which as in any other locationcan be deuterium), deuterium, C₁-C₆alkyl (including C₁-C₃ alkyl),C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆alkoxy, (C₃-C₆cycloalkyl)C₀-C₄alkyl-, (aryl)C₀-C₂alkyl-,(heteroaryl)C₀-C₂alkyl-, or a side chain of an amino acid (i.e., amoiety which is found on the carbon linking the amino group and thecarboxyl group in an amino acid) or its isomer; each of which isoptionally substituted. The R³⁸ and R³⁹ substituents independentlyinclude but are not limited to any corresponding R³⁸ and R³⁹ positionsfound in natural amino acids (or their D-counterpart) (i.e., thesubstituents on the carbon between the carbonyl and the amino group) andnon-proteogenic amino acids, such as serine, threonine, asparagine,glutamine, cysteine, selenocysteine, glycine (e.g., hydrogen), alanine,valine, isoleucine, methionine, phenylalanine, tyrosine, tryptophan,ornithine, glutamine, arginine, histidine, proline, hydroxyproline,selenomethionine, lanthionine, 2-aminoisobutyric acid or dehydroalanine(i.e., R³⁸ or R³⁹ is an exo-double bond), with optional protection offunctional groups such as hydroxyl, amino, thiol, etc.

Pharmaceutical compositions comprising a compound or salt of Formula I,Formula I′ or Formula I″ together with a pharmaceutically acceptablecarrier are also disclosed.

The present invention thus includes at least the following features:

-   (a) a compound of Formula I, Formula I′ or Formula I″ or a    pharmaceutically acceptable salt or prodrug thereof, for use in    treating or preventing a disorder listed in the Detailed    Description, Part IV, including but not limited to the development    of fatty liver and conditions stemming from fatty liver, such as    nonalcoholic steatohepatitis (NASH), liver inflammation, cirrhosis,    or liver failure; dermatomyocitis; amyotrophic lateral sclerosis;    cytokine or inflammatory reactions in response to biotherapeutics    (e.g. CAR T-cell therapy); paroxysmal nocturnal hemoglobinuria    (PNH), rheumatoid arthritis, multiple sclerosis, age-related macular    degeneration (AMD), retinal degeneration, other ophthalmic diseases    (e.g., geographic atrophy), a respiratory disease or a    cardiovascular disease;-   (b) a pharmaceutically acceptable composition of a compound of    Formula I, Formula I′ or Formula I″ or its pharmaceutically    acceptable salt in a pharmaceutically acceptable carrier;-   (c) a compound selected from Formula I, Formula I′ or Formula I″ or    a pharmaceutically acceptable salt or prodrug thereof, for use in    treating or preventing a disorder mediated by the complement    pathway, and for example, cascade Factor D;-   (d) use of a compound of Formula I, Formula I′ or Formula I″, as    described herein, or a pharmaceutically acceptable salt or prodrug    thereof, in the manufacture of a medicament for treating or    preventing a disorder listed in the Detailed Description, Part IV,    including but not limited to the development of fatty liver and    conditions stemming from fatty liver, such as nonalcoholic    steatohepatitis (NASH), liver inflammation, cirrhosis, liver    failure; dermatomyocitis; amyotrophic lateral sclerosis; cytokine or    inflammatory reactions in response to biotherapeutics (e.g. CAR    T-cell therapy); paroxysmal nocturnal hemoglobinuria (PNH),    rheumatoid arthritis, multiple sclerosis, age-related macular    degeneration (AMD), retinal degeneration, other ophthalmic diseases    (e.g., geographic atrophy), a respiratory disease or a    cardiovascular disease;-   (e) a process for manufacturing a medicament intended for the    therapeutic use for treating or preventing a disorder listed in the    Detailed Description, Part IV, or generally for treating or    preventing disorders mediated by complement cascade Factor D,    characterized in that a compound selected from Formula I, Formula I′    or Formula I″ or an embodiment of the active compound is used in the    manufacture;-   (f) a compound selected from Formula I, Formula I′ or Formula I″ or    a salt thereof as described herein in substantially pure form (e.g.,    at least 90 or 95%):-   (g) a compound of Formula I, Formula I′ or Formula I″ as described    herein, or a pharmaceutically acceptable salt or prodrug thereof,    for use in treating a medical disorder which is an inflammatory or    immune condition, a disorder mediated by the complement cascade    (including a dysfunctional cascade), a disorder or abnormality of a    cell that adversely affects the ability of the cell to engage in or    respond to normal complement activity, or an undesired    complement-mediated response to a medical treatment, such as surgery    or other medical procedure or a pharmaceutical or biopharmaceutical    drug administration, a blood transfusion, or other allogenic tissue    or fluid administration.-   (h) For each of (a) through (g) above, and otherwise herein, each    assembly of moieties in the Figures and each active compound made    therefrom or its use is considered and deemed specifically and    individually disclosed, as such depiction is for convenience of    space only and not intended to describe a only a genus or even a    subgenus for such indication.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 provides non-limiting specific embodiments of the Central Corering, wherein R, R′, and R³ are defined below.

FIGS. 2A, 2B, 2C, 2D, 2E, 2F, 2G, 2H, 2I, 2J, 2K, 2L, and 2M, providenon-limiting embodiments of C1′, wherein R³ is as defined herein.

FIG. 3 provides non-limiting embodiments of C2.

FIGS. 4A, 4B, 4C, 4D, 4E, 4F, 4G, 4H, 4I, 4J, 4K, 4L, 4M, and 4N,provide non-limiting embodiments of C3.

FIG. 5 provides non-limiting embodiments of central core small mimeticsof a beta-turn, beta turn inducers, reverse turn mimetics and foldamermonomers.

FIG. 6 provides non-limiting embodiments of A1′, wherein R³² is definedbelow.

FIGS. 7A, 7B, 7C, 7D, and 7E, provide non-limiting embodiments of A2,wherein R³² is defined below.

FIGS. 8A, 8B, 8C, and 8D, provide non-limiting embodiments of L1′.

FIGS. 9A, 9B, 9C, 9D, 9E, 9F, 9G, 9H, 9I, and 9J, provide non-limitingembodiments of L2.

FIGS. 10A, 10B, 10C, and 10D, provide non-limiting specific embodimentsof B1 rings, wherein R²⁷, R²⁸, and R²⁹ are defined below.

FIGS. 11A, 11B, 11C, 11D, provide non-limiting specific embodiments ofB1′ rings, wherein halo is selected from F, Cl, Br, or I.

FIG. 12 provides specific embodiments of B2 rings.

FIGS. 13A, 13B, 13C, 13D, 13E, 13F, 13G, 13H, 13I, 13J, 13K, 13L, 13M,13N, 13O, 13P, 13Q, 13R, 13S, 13T, 13U, 13V, 13W, 13X, 13Y, and 13Z,provide specific embodiments of B3 moieties.

FIG. 14 provides non-limiting embodiments of L2-B3 wherein B3 is R²¹,and R²¹ is defined below.

FIGS. 15A and 15B provide non-limiting embodiments of R³².

FIGS. 16A, 16B, 16C, 16D, 16E, 16F, 16G, 16H, 16I, 16J, 16K, 16L, 16M,and 16N provide non-limiting examples of compounds included in thepresent invention, wherein Z₃₂ is the same as R³² as used herein.

DETAILED DESCRIPTION I. Terminology

Compounds are described using standard nomenclature. Unless definedotherwise, all technical and scientific terms used herein have the samemeaning as is commonly understood by one of skill in the art to whichthis invention belongs.

The compounds in any of the Formulas described herein includeenantiomers, mixtures of enantiomers, diastereomers, tautomers,racemates and other isomers, such as rotamers, as if each isspecifically described, unless otherwise indicated or otherwise clearfrom the context.

The terms “a” and “an” do not denote a limitation of quantity, butrather denote the presence of at least one of the referenced item. Theterm “or” means “and/or”. Recitation of ranges of values are merelyintended to serve as a shorthand method of referring individually toeach separate value falling within the range, unless otherwise indicatedherein, and each separate value is incorporated into the specificationas if it were individually recited herein. The endpoints of all rangesare included within the range and independently combinable. All methodsdescribed herein can be performed in a suitable order unless otherwiseindicated herein or otherwise clearly contradicted by context. The useof examples, or exemplary language (e.g., “such as”), is intended merelyto better illustrate the invention and does not pose a limitation on thescope of the invention unless otherwise claimed. Unless definedotherwise, technical and scientific terms used herein have the samemeaning as is commonly understood by one of skill in the art to whichthis invention belongs.

The present invention includes compounds of Formula I, Formula I′ orFormula I″ with at least one desired isotopic substitution of an atom,at an amount above the natural abundance of the isotope, i.e., enriched.Isotopes are atoms having the same atomic number but different massnumbers, i.e., the same number of protons but a different number ofneutrons.

Examples of isotopes that can be incorporated into compounds of theinvention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N,¹⁸F, ³¹P, ³²P, ³⁵S, ³⁶Cl, ¹²⁵I respectively. In one embodiment,isotopically labelled compounds can be used in metabolic studies (with¹⁴C), reaction kinetic studies (with, for example ²H or ³H), detectionor imaging techniques, such as positron emission tomography (PET) orsingle-photon emission computed tomography (SPECT) including drug orsubstrate tissue distribution assays, or in radioactive treatment ofpatients. In particular, an ¹⁸F labeled compound may be particularlydesirable for PET or SPECT studies. Isotopically labeled compounds ofthis invention and prodrugs thereof can generally be prepared bycarrying out the procedures disclosed in the schemes or in the examplesand preparations described below by substituting a readily availableisotopically labeled reagent for a non-isotopically labeled reagent.

By way of general example and without limitation, isotopes of hydrogen,for example, deuterium (²H) and tritium (³H) may be used anywhere indescribed structures that achieves the desired result. Alternatively orin addition, isotopes of carbon, e.g., ¹³C and ¹⁴C, may be used. In oneembodiment, the isotopic substitution is deuterium for hydrogen at oneor more locations on the molecule to improve the performance of thedrug, for example, the pharmacodynamics, pharmacokinetics,biodistribution, half-life, stability, AUC, Tmax, Cmax, etc. Forexample, the deuterium can be bound to carbon in a location of bondbreakage during metabolism (an α-deuterium kinetic isotope effect) ornext to or near the site of bond breakage (a β-deuterium kinetic isotopeeffect).

Isotopic substitutions, for example deuterium substitutions, can bepartial or complete. Partial deuterium substitution means that at leastone hydrogen is substituted with deuterium. In certain embodiments, theisotope is 90, 95 or 99% or more enriched in an isotope at any locationof interest. In one embodiments deuterium is 90, 95 or 99% enriched at adesired location. Unless otherwise stated, the enrichment at any pointis above natural abundance and enough to alter a detectable property ofthe drug in a human.

In one embodiment, the substitution of a hydrogen atom for a deuteriumatom can be provided in any of A1, A1′, A2, B1, B1′, B2, B3, B4, C1,C1′, C2, C3, C4, L1, L1′, L2, L2′, L4 or L5. In one embodiment, thesubstitution of a hydrogen atom for a deuterium atom occurs within an Rgroup selected from any of R, R′, R¹, R^(1′), R², R^(2′), R³, R^(3′),R⁴, R⁵, R⁶, R^(6′), R⁷, R⁸, R^(8′), R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁹,R²¹, R²², R²³, R³¹, R³², R³³, R³⁴, R³⁵, R³⁶, R³⁷, R³⁸, R³⁹, R⁴, R⁴¹,R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷, R⁴⁸, R⁴⁹, R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴, R¹⁰¹,or R¹⁰². For example, when any of R groups are, or contain for examplethrough substitution, methyl, ethyl, or methoxy, the alkyl residue maybe deuterated (in nonlimiting embodiments, CD₃, CH₂CD₃, CD₂CD₃, CDH₂,CD₂H, CD₃, CHDCH₂D, CH₂CD₃, CHDCHD₂, OCDH₂, OCD₂H, or OCD₃ etc.). Incertain embodiments, an R group has a “′” or an “a” designation, whichin one embodiment can be deuterated. In certain other embodiments, whentwo substituents of the central core ring are combined to form acyclopropyl ring, the unsubstituted methylene carbon may be deuterated.

The compound of the present invention may form a solvate with solvents(including water). Therefore, in one embodiment, the invention includesa solvated form of the active compound. The term “solvate” refers to amolecular complex of a compound of the present invention (including asalt thereof) with one or more solvent molecules. Nonlimiting examplesof solvents are water, ethanol, dimethyl sulfoxide, acetone and othercommon organic solvents. The term “hydrate” refers to a molecularcomplex comprising a compound of the invention and water.Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO. A solvate can be in a liquidor solid form.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —(C═O)NH₂is attached through carbon of the keto (C═O) group.

The term “substituted”, as used herein, means that any one or morehydrogens on the designated atom or group is replaced with a moietyselected from the indicated group, provided that the designated atom'snormal valence is not exceeded and the resulting compound is stable. Forexample, when the substituent is oxo (i.e., ═O) then two hydrogens onthe atom are replaced. For example a pyridyl group substituted by oxo isa pyridone. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds oruseful synthetic intermediates.

A stable active compound refers to a compound that can be isolated andcan be formulated into a dosage form with a shelf life of at least onemonth. A stable manufacturing intermediate or precursor to an activecompound is stable if it does not degrade within the period needed forreaction or other use. A stable moiety or substituent group is one thatdoes not degrade, react or fall apart within the period necessary foruse. Nonlimiting examples of unstable moieties are those that combineheteroatoms in an unstable arrangement, as typically known andidentifiable to those of skill in the art.

Any suitable group may be present on a “substituted” or “optionallysubstituted” position that forms a stable molecule and meets the desiredpurpose of the invention and includes, but is not limited to, e.g.,halogen (which can independently be F, Cl, Br or I); cyano; hydroxyl;nitro; azido; alkanoyl (such as a C₂-C₆ alkanoyl group); carboxamide;alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy such as phenoxy;alkylthio including those having one or more thioether linkages;alkylsulfinyl; alkylsulfonyl groups including those having one or moresulfonyl linkages; aminoalkyl groups including groups having one or moreN atoms; aryl (e.g., phenyl, biphenyl, naphthyl, or the like, each ringeither substituted or unsubstituted aromatic); arylalkyl having forexample, 1 to 3 separate or fused rings and from 6 to about 14 or 18ring carbon atoms, with benzyl being an exemplary arylalkyl group;arylalkoxy, for example, having 1 to 3 separate or fused rings withbenzyloxy being an exemplary arylalkoxy group; or a saturated,unsaturated, or aromatic heterocyclic group having 1 to 3 separate orfused rings with one or more N, O or S atoms, e.g. coumarinyl,quinolinyl, isoquinolinyl, quinazolinyl, pyridyl, pyrazinyl,pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, triazinyl, oxazolyl,isoxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl,tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl,piperazinyl, and pyrrolidinyl. Such heterocyclic groups may be furthersubstituted, e.g. with hydroxy, alkyl, alkoxy, halogen and amino. Incertain embodiments “optionally substituted” includes one or moresubstituents independently selected from halogen, hydroxyl, amino,cyano, —CHO, —COOH, —CONH₂, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,—C₁-C₆alkoxy, C₂-C₆alkanoyl, C₁-C₆alkylester, (mono- anddi-C₁-C₆alkylamino)C₀-C₂alkyl, C₁-C₂haloalkyl, hydoxyC₁-C₆alkyl, ester,carbamate, urea, sulfonamide, —C₁-C₆alkyl(heterocyclo),C₁-C₆alkyl(heteroaryl), —C₁-C₆alkyl(C₃-C₇cycloalkyl),O—C₁-C₆alkyl(C₃-C₇cycloalkyl), B(OH)₂, phosphate, phosphonate andC₁-C₂haloalkoxy.

“Alkyl” is a branched or straight chain saturated aliphatic hydrocarbongroup. In one embodiment, the alkyl contains from 1 to about 12 carbonatoms, more generally from 1 to about 6 carbon atoms or from 1 to about4 carbon atoms. In one embodiment, the alkyl contains from 1 to about 8carbon atoms. In certain embodiments, the alkyl is C₁-C₂, C₁-C₃, C₁-C₄,C₁-C₅ or C₁-C₆. The specified ranges as used herein indicate an alkylgroup having each member of the range described as an independentspecies. For example, the term C₁-C₆ alkyl as used herein indicates astraight or branched alkyl group having from 1, 2, 3, 4, 5, or 6 carbonatoms and is intended to mean that each of these is described as anindependent species. For example, the term C₁-C₄alkyl as used hereinindicates a straight or branched alkyl group having from 1, 2, 3, or 4carbon atoms and is intended to mean that each of these is described asan independent species. When C₀-C_(n) alkyl is used herein inconjunction with another group, for example, (C₃-C₇cycloalkyl)C₀-C₄alkyl, or —C₀-C₄alkyl(C₃-C₇cycloalkyl), the indicated group, in thiscase cycloalkyl, is either directly bound by a single covalent bond(C₀alkyl), or attached by an alkyl chain in this case 1, 2, 3, or 4carbon atoms. Alkyls can also be attached via other groups such asheteroatoms as in —O—C₀-C₄alkyl(C₃-C₇cycloalkyl). Examples of alkylinclude, but are not limited to, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl,neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane,2,2-dimethylbutane, 2,3-dimethylbutane, and hexyl. In one embodiment,the alkyl group is optionally substituted as described above. In oneembodiment, trimethylsilyl can be used instead of t-butyl.

In one embodiment, when a term is used that includes “alk” it should beunderstood that “cycloalkyl” or “carbocyclic” can be considered part ofthe definition, unless unambiguously excluded by the context. Forexample and without limitation, the terms alkyl, alkenyl, alkynyl,alkoxy, alkanoyl, alkenloxy, haloalkyl, aminoalkyl, alkylene,alkenylene, alkynylene, etc. can all be considered to include the cyclicforms of alkyl, unless unambiguously excluded by context.

“Alkenyl” is a branched or straight chain aliphatic hydrocarbon grouphaving one or more carbon-carbon double bonds that may occur at a stablepoint along the chain. Nonlimiting examples are C₂-C₈alkenyl,C₂-C₇alkenyl, C₂-C₆alkenyl, C₂-C₈alkenyl and C₂-C₄alkenyl. The specifiedranges as used herein indicate an alkenyl group having each member ofthe range described as an independent species, as described above forthe alkyl moiety. Examples of alkenyl include, but are not limited to,ethenyl and propenyl. In one embodiment, the alkenyl group is optionallysubstituted as described above.

“Alkynyl” is a branched or straight chain aliphatic hydrocarbon grouphaving one or more carbon-carbon triple bonds that may occur at anystable point along the chain, for example, C₂-C₈alkynyl or C₂-C₆alkynyl.The specified ranges as used herein indicate an alkynyl group havingeach member of the range described as an independent species, asdescribed above for the alkyl moiety. Examples of alkynyl include, butare not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl,1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl,3-hexynyl, 4-hexynyl and 5-hexynyl. In one embodiment, the alkynyl groupis optionally substituted as described above.

“Alkylene” is a bivalent saturated hydrocarbon. Alkylenes, for example,can be a 1, 2, 3, 4, 5, 6, 7 to 8 carbon moiety, 1 to 6 carbon moiety,or an indicated number of carbon atoms, for example C₁-C₂alkylene,C₁-C₃alkylene, C₁-C₄alkylene, C₁-C₅alkylene, or C₁-C₆alkylene.

“Alkenylene” is a bivalent hydrocarbon having at least one carbon-carbondouble bond. Alkenylenes, for example, can be a 2 to 8 carbon moiety, 2to 6 carbon moiety, or an indicated number of carbon atoms, for exampleC₂-C₄alkenylene.

“Alkynylene” is a bivalent saturated hydrocarbon. Alkynylenes, forexample, can be a 2 to 8 carbon moiety, 2 to 6 carbon moiety, or anindicated number of carbon atoms, for example C₂-C₄alkynylene.

“Alkoxy” is an alkyl group as defined above covalently bound through anoxygen bridge (—O—). Examples of alkoxy include, but are not limited to,methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy,n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy,2-hexoxy, 3-hexoxy, and 3-methylpentoxy. Similarly an “alkylthio” or a“thioalkyl” group is an alkyl group as defined above with the indicatednumber of carbon atoms covalently bound through a sulfur bridge (—S—).In one embodiment, the alkoxy group is optionally substituted asdescribed above.

“Alkenyloxy” is an alkenyl group as defined covalently bound to thegroup it substitutes by an oxygen bridge (—O—).

“Alkanoyl” is an alkyl group as defined above covalently bound through acarbonyl (C═O) bridge. The carbonyl carbon is included in the number ofcarbons, that is C₂alkanoyl is a CH₃(C═O)— group. In one embodiment, thealkanoyl group is optionally substituted as described above.

“Alkylester” is an alkyl group as defined herein covalently boundthrough an ester linkage. The ester linkage may be in eitherorientation, e.g., a group of the formula —O(C═O)alkyl or a group of theformula —(C═O)Oalkyl.

“Amide” or “carboxamide” is —C(O)NR^(a)R^(b) wherein R^(a) and R^(b) areeach independently selected from hydrogen, alkyl, for example,C₁-C₆alkyl, alkenyl, for example, C₂-C₆alkenyl, alkynyl, for example,C₂-C₆alkynyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl),—C₀-C₄alkyl(C₃-C₇heterocycloalkyl), —C₀-C₄alkyl(aryl), and—C₀-C₄alkyl(heteroaryl); or together with the nitrogen to which they arebonded, R^(a) and R^(b) can form a C₃-C₇heterocyclic ring. In oneembodiment, the R^(a) and R^(b) groups are each independently optionallysubstituted as described herein.

“Carbocyclic group”, “carbocyclic ring”, or “cycloalkyl” is a saturatedor partially unsaturated (i.e., not aromatic) group containing allcarbon ring atoms. A carbocyclic group typically contains 1 ring of 3 to7 carbon atoms or 2 fused rings each containing 3 to 7 carbon atoms.Cycloalkyl substituents may be pendant from a substituted nitrogen orcarbon atom, or a substituted carbon atom that may have two substituentscan have a cycloalkyl group, which is attached as a spiro group.Examples of carbocyclic rings include cyclohexenyl, cyclohexyl,cyclopentenyl, cyclopentyl, cyclobutenyl, cyclobutyl and cyclopropylrings. In one embodiment, the carbocyclic ring is optionally substitutedas described above. In one embodiment, the cycloalkyl is a partiallyunsaturated (i.e., not aromatic) group containing all carbon ring atoms.In another embodiment, the cycloalkyl is a saturated group containingall carbon ring atoms.

“Carbocyclic-oxy group” is a monocyclic carbocyclic ring or a mono- orbi-cyclic carbocyclic group as defined above attached to the group itsubstitutes via an oxygen, —O—, linker.

“Haloalkyl” indicates both branched and straight-chain alkyl groupssubstituted with 1 or more halogen atoms, up to the maximum allowablenumber of halogen atoms. Examples of haloalkyl include, but are notlimited to, trifluoromethyl, monofluoromethyl, difluoromethyl,2-fluoroethyl, and penta-fluoroethyl.

“Haloalkoxy” indicates a haloalkyl group as defined herein attachedthrough an oxygen bridge (oxygen of an alcohol radical).

“Hydroxyalkyl” is an alkyl group as previously described, substitutedwith at least one hydroxyl substituent.

“Aminoalkyl” is an alkyl group as previously described, substituted withat least one amino substituent.

“Halo” or “halogen” indicates independently, any of fluoro, chloro,bromo or iodo.

“Aryl” indicates an aromatic group containing only carbon in thearomatic ring or rings. In one embodiment, the aryl group contains 1 to3 separate or fused rings and is 6 to about 14 or 18 ring atoms, withoutheteroatoms as ring members. When indicated, such aryl groups may befurther substituted with carbon or non-carbon atoms or groups. Suchsubstitution may include fusion to a 4 to 7 or a 5 to 7-memberedsaturated or partially unsaturated cyclic group that optionally contains1, 2 or 3 heteroatoms independently selected from N, O, B, P, Si and/orS, to form, for example, a 3,4-methylenedioxyphenyl group. Aryl groupsinclude, for example, phenyl and naphthyl, including 1-naphthyl and2-naphthyl. In one embodiment, aryl groups are pendant. An example of apendant ring is a phenyl group substituted with a phenyl group. In oneembodiment, the aryl group is optionally substituted as described above.

The term “heterocycle,” or “heterocyclic ring” as used herein refers toa saturated or a partially unsaturated (i.e., having one or more doubleand/or triple bonds within the ring without aromaticity) carbocyclicmoiety of 3 to about 12, and more typically 3, 4, 5, 6, 7, 8 to 10 ringatoms in which at least one ring atom is a heteroatom selected fromnitrogen, oxygen, phosphorus, sulfur, silicon and boron, the remainingring atoms being C, where one or more ring atoms is optionallysubstituted independently with one or more substituents described above.A heterocycle may be a monocycle having 3 to 7 ring members (2 to 6carbon atoms and 1 to 4 heteroatoms selected from N, O, P, S, Si and B)or a bicycle having 6 to 10 ring members (4 to 9 carbon atoms and 1 to 6heteroatoms selected from N, O, P, S, Si and B), for example: a bicyclo[4,5], [5,5], [5,6], or [6,6] system. In one embodiment, the onlyheteroatom is nitrogen. In one embodiment, the only heteroatom isoxygen. In one embodiment, the only heteroatom is sulfur, boron orsilicon. Heterocycles are described in Paquette, Leo A.; “Principles ofModern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968),particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry ofHeterocyclic Compounds, A series of Monographs” (John Wiley & Sons, NewYork, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28;and J. Am. Chem. Soc. (1960) 82:5566. Examples of heterocyclic ringsinclude, but are not limited to, pyrrolidinyl, dihydrofuranyl,tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl,tetrahydrothiopyranyl, piperidino, piperidonyl, morpholino,thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl,oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl,diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl,2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl,dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl,dihydroisoquinolinyl, tetrahydroisoquinolinyl,pyrazolidinylimidazolinyl, imidazolidinyl,2-oxa-5-azabicyclo[2.2.2]octane, 3-oxa-8-azabicyclo[3.2.1]octane,8-oxa-3-azabicyclo[3.2.1]octane, 6-oxa-3-azabicyclo[3.1.1]heptane,2-oxa-5-azabicyclo[2.2.1]heptane, 3-azabicyco[3.1.0]hexanyl,3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indolyl,quinolizinyl, N-pyridyl ureas, and pyrrolopyrimidine. Spiro moieties arealso included within the scope of this definition. Examples of aheterocyclic group wherein 1 or 2 ring carbon atoms are substituted withoxo (═O) moieties are pyrimidinonyl and 1,1-dioxo-thiomorpholinyl. Theheterocycle groups herein are optionally substituted independently withone or more substituents described herein, for example, 1, 2 or 3substituents.

“Heterocyclicoxy group” is a monocyclic heterocyclic ring or a bi-cyclicheterocyclic group as described previously linked to the group itsubstitutes via an oxygen, —O—, linker.

“Heteroaryl” refers to a stable monocyclic aromatic ring which containsfrom 1 to 3, or in some embodiments from 1, 2 or 3 heteroatoms selectedfrom N, O, S, B or P with remaining ring atoms being carbon, or a stablebicyclic or tricyclic system containing at least one 5, 6 or 7 memberedaromatic ring which contains from 1 to 3, or in some embodiments from 1to 2, heteroatoms selected from N, O, S, B or P with remaining ringatoms being carbon. In one embodiment, the only heteroatom is nitrogen.In one embodiment, the only heteroatom is oxygen. In one embodiment, theonly heteroatom is sulfur. Monocyclic heteroaryl groups typically havefrom 5, 6 or 7 ring atoms. In some embodiments bicyclic heteroarylgroups are 8- to 10-membered heteroaryl groups, that is, groupscontaining 9 or 10 ring atoms in which one 5, 6 or 7 member aromaticring is fused to a second aromatic or non-aromatic ring. When the totalnumber of S and O atoms in the heteroaryl group exceeds 1, theseheteroatoms are not adjacent to one another. In one embodiment, thetotal number of S and O atoms in the heteroaryl group is not more than2. In another embodiment, the total number of S and O atoms in thearomatic heterocycle is not more than 1. Examples of heteroaryl groupsinclude, but are not limited to, pyridinyl (including, for example,2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl(including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl,pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl,isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl,benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl,pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl,triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl,benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl,quinoxalinyl, naphthyridinyl, tetrahydrofuranyl, and furopyridinyl.Heteroaryl groups are optionally substituted independently with one ormore substituents described herein. “Heteroaryloxy” is a heteroarylgroup as described bound to the group it substituted via an oxygen, —O—,linker.

“Heterocycloalkyl” is a saturated ring group. It may have, for example,1, 2, 3, or 4 heteroatoms independently selected from N, S, O, Si and Bwith remaining ring atoms being carbon. In a typical embodiment,nitrogen is the heteroatom. Monocyclic heterocycloalkyl groups typicallyhave from 3 to about 8 ring atoms or from 4 to 6 ring atoms. Examples ofheterocycloalkyl groups include morpholinyl, piperazinyl, piperidinyl,and pyrrolinyl.

The term “mono- and/or di-alkylamino” indicate a secondary or tertiaryalkylamino group, wherein the alkyl groups are independently selectedalkyl groups, as defined herein. The point of attachment of thealkylamino group is on the nitrogen. Examples of mono- and di-alkylaminogroups include ethylamino, dimethylamino, and methyl-propyl-amino.

A “dosage form” means a unit of administration of an active agent.Examples of dosage forms include tablets, capsules, injections,suspensions, liquids, emulsions, implants, particles, spheres, creams,ointments, suppositories, inhalable forms, transdermal forms, buccal,sublingual, topical, gel, mucosal, and the like. A “dosage form” canalso include an implant, for example an optical implant.

“Pharmaceutical compositions” are compositions comprising at least oneactive agent, and at least one other substance, such as a carrier.“Pharmaceutical combinations” are combinations of at least two activeagents which may be combined in a single dosage form or providedtogether in separate dosage forms with instructions that the activeagents are to be used together to treat any disorder described herein.

A “pharmaceutically acceptable salt” is a derivative of the disclosedcompound in which the parent compound is modified by making inorganicand organic, pharmaceutically acceptable, acid or base addition saltsthereof. The salts of the present compounds can be synthesized from aparent compound that contains a basic or acidic moiety by conventionalchemical methods. Generally, such salts can be prepared by reacting freeacid forms of these compounds with a stoichiometric amount of theappropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate,bicarbonate, or the like), or by reacting free base forms of thesecompounds with a stoichiometric amount of the appropriate acid. Suchreactions are typically carried out in water or in an organic solvent,or in a mixture of the two. Generally, non-aqueous media like ether,ethyl acetate, ethanol, isopropanol, or acetonitrile are typical, wherepracticable. Salts of the present compounds further include solvates ofthe compounds and of the compound salts.

Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts include theconventional non-toxic salts and the quaternary ammonium salts of theparent compound formed, for example, from non-toxic inorganic or organicacids. For example, conventional non-toxic acid salts include thosederived from inorganic acids such as hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric, nitric and the like; and the saltsprepared from organic acids such as acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,HOOC—(CH₂)_(n)—COOH where n is 0-4, and the like, or using a differentacid that produces the same counterion. Lists of additional suitablesalts may be found, e.g., in Remington's Pharmaceutical Sciences, 17thed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).

The term “carrier” applied to pharmaceutical compositions/combinationsof the invention refers to a diluent, excipient, or vehicle with whichan active compound is provided.

A “pharmaceutically acceptable excipient” means an excipient that isuseful in preparing a pharmaceutical composition/combination that isgenerally safe, non-toxic and neither biologically nor otherwiseinappropriate for administration to a host, typically a human. In oneembodiment, an excipient is used that is acceptable for veterinary use.

A “patient” or “host” or “subject” is a human or non-human animal inneed of treatment or prevention of any of the disorders as specificallydescribed herein, including but not limited to by modulation of thecomplement Factor D pathway. Typically the host is a human. A “patient”or “host” or “subject” also refers to for example, a mammal, primate(e.g., human), cows, sheep, goat, horse, dog, cat, rabbit, rat, mice,fish, bird and the like.

A “prodrug” as used herein, means a compound which when administered toa host in vivo is converted into a parent drug. As used herein, the term“parent drug” means any of the presently described chemical compoundsdescribed herein. Prodrugs can be used to achieve any desired effect,including to enhance properties of the parent drug or to improve thepharmaceutic or pharmacokinetic properties of the parent. Prodrugstrategies exist which provide choices in modulating the conditions forin vivo generation of the parent drug, all of which are deemed includedherein. Nonlimiting examples of prodrug strategies include covalentattachment of removable groups, or removable portions of groups, forexample, but not limited to acylation, phosphorylation, phosphonylation,phosphoramidate derivatives, amidation, reduction, oxidation,esterification, alkylation, other carboxy derivatives, sulfoxy orsulfone derivatives, carbonylation or anhydride, among others.

“Providing a compound with at least one additional active agent” meansthe compound and the additional active agent(s) are providedsimultaneously in a single dosage form, provided concomitantly inseparate dosage forms, or provided in separate dosage forms foradministration separated by some amount of time that is within the timein which both the compound and the at least one additional active agentare within the blood stream or other target area of a patient. Incertain embodiments the compound and the additional active agent neednot be prescribed for a patient by the same medical care worker. Incertain embodiments the additional active agent or agents need notrequire a prescription. Administration of the compound or the at leastone additional active agent can occur via any appropriate route, forexample, oral tablets, oral capsules, oral liquids, inhalation,injection, suppositories, parenteral, sublingual, buccal, intravenous,intraaortal, transdermal, polymeric controlled delivery, non-polymericcontrolled delivery, nano or microparticles, liposomes, and/or topicalcontact. In one embodiment, the instructions for administration in aform of combination therapy is provided in the drug labeling.

A “therapeutically effective amount” of a pharmaceuticalcomposition/combination of this invention means an amount effective,when administered to a host, to provide a therapeutic benefit such as anamelioration of symptoms or reduction or dimunition of the diseaseitself. In one embodiment, a therapeutically effective amount is anamount sufficient to prevent a significant increase or willsignificantly reduce the detectable level of complement Factor D in thepatient's blood, serum, or tissues.

II. Detailed Description of the Active Compounds

According to the present invention, a compound of Formula I is provided:

as well as the pharmaceutically acceptable salts and compositionsthereof. Formula I can be considered to have a central core C, an Lsubstituent, a B substituent, and a L3-A substituent. Formula Icomprises at least one of the A2, B3, C3, L2, L2′ or L5 moietiesdescribed herein. In an alternative embodiment, Formula I can include amoiety from C4. The invention includes a compound of Formula I, or apharmaceutically acceptable salt or composition thereof, wherein R¹² orR¹³ on the A group is an amino substituent, for example an R³². In oneembodiment, the compound is an inhibitor of complement factor D, andtherefore can be used as an effective amount to treat a host in need ofcomplement factor D modulation. In another embodiment, the compound actsthrough a mechanism other than inhibition of complement D to treat adisorder described herein in a host, typically a human.

The present invention also includes a compound of Formula I′:

as well as the pharmaceutically acceptable salts and compositionsthereof. Formula I′ has a central core, an A substituent, a L3substituent, a L substituent, a B substituent and a —X⁹—(CH₂)_(p)—X¹⁰linker; wherein R¹² or R¹³ on the A1 or A2 group is an an aminosubstituent, for example a R³² as a divalent moiety. In one embodiment,this compound is an inhibitor of complement factor D, and therefore canbe used as an effective amount to treat a host in need of complementfactor D modulation. Alternatively, the compound may act through adifferent mechanism of action to treat the disorders described herein.

In addition, the present invention provides a compound of Formula I″:

as well as the pharmaceutically acceptable salts and compositionsthereof. Formula I″ has an

moiety, an A substituent, a L3 substituent, a L substituent and a Bsubstituent. Compounds of Formula I″, or a pharmaceutically acceptablesalt or composition thereof, wherein R¹² or R¹³ on the A1 or A2 group isan an amino substituent, for example an R³². In one embodiment, thiscompound is an inhibitor of complement factor D, and therefore can beused as an effective amount to treat a host in need of complement factorD modulation. Alternatively, the compound may act through a differentmechanism of action to treat the disorders described herein.

Non-limiting examples of compounds falling within Formula I and FormulaI′ with variations in the variables e.g., A, B, R¹-R^(3′), and L, aredescribed below.

Non-limiting examples of compounds falling within Formula I″ withvariations in the variables e.g., R³⁷, R³⁸, R³⁹, A, B, L and L3 aredescribed below. The disclosure includes all combinations of thesedefinitions as long as a stable compound results.

In certain embodiments, any of the active compounds can be provided inits N-oxide form to a patient in need thereof. In a differentembodiment, an N-oxide of one of the active compounds or a precursor ofthe active compound is used in a manufacturing scheme. In yet anotherembodiment, the N-oxide is a metabolite of administration of one of theactive compounds herein, and may have independent activity. The N-oxidecan be formed by treating the compound of interest with an oxidizingagent, for example a suitable peroxyacid or peroxide, to generate anN-oxide compound. For example, a heteroaryl group, for example a pyridylgroup, can be treated with an oxidizing agent such as sodiumpercarbonate in the presence of a rhenium-based catalyst under mildreaction conditions to generate an N-oxide compound. A person skilled inthe art will understand that appropriate protecting groups may benecessary to carry out the chemistry. See, Jain, S. L. et al.,“Rhenium-Catalyzed Highly Efficient Oxidations of Tertiary NitrogenCompounds to N-Oxides Using Sodium Percarbonate as Oxygen Source,Synett, 2261-2663, 2006.

In other embodiments, any of the active compounds with a sulfur can beprovided in its sulfoxide or sulfone form to a patient in need thereof.In a different embodiment, a sulfoxide or sulfone of one of the activecompounds or a precursor of the active compound is used in amanufacturing scheme. A sulfur atom in a selected compound as describedherein can be oxidized to form a sulfoxide

or a sulfone

using known methods. For example, the compound1,3,5-triazo-2,4,6-triphosphorine-2,2,4,4,6,6-tetrachloride (TAPC) is anefficient promoter for the oxidation of sulfides to sulfoxides. See,Bahrami, M, et al., “TAPC-Promoted Oxidation of sulfides andDeoxygenation of Sulfoxides”, J. Org. Chem., 75, 6208-6213 (2010).Oxidation of sulfides with 30% hydrogen peroxide catalyzed by tantalumcarbide provides sulfoxides in high yields, see, Kirihara, A., et al.,“Tantalum Carbide or Niobium Carbide Catalyzed Oxidation of Sulfideswith Hydrogen Peroxide: Highly Efficient and Chemoselective Syntheses ofSulfoxides and Sulfones”, Synlett, 1557-1561 (2010). Sulfides can beoxidized to sulfones using, for example, niobium carbide as thecatalyst, see, Kirihara, A., et al., “Tantalum Cardide or NiobiumCarbide Catalyzed Oxidation of Sulfides with Hydrogen Peroxide: HighlyEfficient and Chemoselective Syntheses of Sulfoxides and Sulfones”,Synlett, 1557-1561 (2010). Urea-hydrogen peroxide adduct is a stableinexpensive and easily handled reagent for the oxidation of sulfides tosulfones, see Varma, R. S. and Naicker, K. P., “The Urea-HydrogenPeroxide Complex: Solid-State Oxidative Protocols for HydroxylatedAldehydes and Ketones (Dakin Reaction), Nitriles, Sulfides, and NitrogenHeterocycles”, Org. Lett., 1, 189-191 (1999). One skilled in the artwill appreciate that other heteroatoms, such as nitrogen, may need to beprotected and then deprotected while carrying out the oxidation of asulfur atom to produce the desired compound.Formulas 2 Through 654

In one aspect, the disclosure includes compounds and salts of Formulas2-654 for any use and in any composition described in this application.

TABLE 1 Exemplary Compounds within the Present Invention. Formula No.Formula 2 A1L4C1L1B3 3 A1L4C1L1′B3 4 A1L4C1L2B1 5 A1L4C1L2B1′ 6A1L4C1L2B2 7 A1L4C1L2B3 8 A1L4C1′L1B3 9 A1L4C1′L1′B3 10 A1L4C1′L2B1 11A1L4C1′L2B1′ 12 A1L4C1′L2B2 13 A1L4C1′L2B3 14 A1L4C2L1B3 15 A1L4C2L1′B316 A1L4C2L2B1 17 A1L4C2L2B1′ 18 A1L4C2L2B2 19 A1L4C2L2B3 20 A1L4C3L1B121 A1L4C3L1B1′ 22 A1L4C3L1B2 23 A1L4C3L1B3 24 A1L4C3L1′B1 25A1L4C3L1′B1′ 26 A1L4C3L1′B2 27 A1L4C3L1′B3 28 A1L4C3L2B1 29 A1L4C3L2B1′30 A1L4C3L2B2 31 A1L4C3L2B3 32 A1L5C1L1B1 33 A1L5C1L1B1′ 34 A1L5C1L1B235 A1L5C1L1B3 36 A1L5C1L1′B1 37 A1L5C1L1′B1′ 38 A1L5C1L1′B2 39A1L5C1L1′B3 40 A1L5C1L2B1 41 A1L5C1L2B1′ 42 A1L5C1L2B2 43 A1L5C1L2B3 44A1L5C1′L1B1 45 A1L5C1′L1B1′ 46 A1L5C1′L1B2 47 A1L5C1′L1B3 48A1L5C1′L1′B1 49 A1L5C1′L1′B1′ 50 A1L5C1′L1′B2 51 A1L5C1′L1′B3 52A1L5C1′L2B1 53 A1L5C1′L2B1′ 54 A1L5C1′L2B2 55 A1L5C1′L2B3 56 A1L5C2L1B157 A1L5C2L1B1′ 58 A1L5C2L1B2 59 A1L5C2L1B3 60 A1L5C2L1′B1 61A1L5C2L1′B1′ 62 A1L5C2L1′B2 63 A1L5C2L1′B3 64 A1L5C2L2B1 65 A1L5C2L2B1′66 A1L5C2L2B2 67 A1L5C2L2B3 68 A1L5C3L1B1 69 A1L5C3L1B1′ 70 A1L5C3L1B271 A1L5C3L1B3 72 A1L5C3L1′B1 73 A1L5C3L1′B1′ 74 A1L5C3L1′B2 75A1L5C3L1′B3 76 A1L5C3L2B1 77 A1L5C3L2B1′ 78 A1L5C3L2B2 79 A1L5C3L2B3 80A1′L4C1L1B3 81 A1′L4C1L1′B3 82 A1′L4C1L2B1 83 A1′L4C1L2B1′ 84A1′L4C1L2B2 85 A1′L4C1L2B3 86 A1′L4C1′L1B3 87 A1′L4C1′L1′B3 88A1′L4C1′L2B1 89 A1′L4C1′L2B1′ 90 A1′L4C1′L2B2 91 A1′L4C1′L2B3 92A1′L4C2L1B3 93 A1′L4C2L1′B3 94 A1′L4C2L2B1 95 A1′L4C2L2B1′ 96A1′L4C2L2B2 97 A1′L4C2L2B3 98 A1′L4C3L1B1 99 A1′L4C3L1B1′ 100A1′L4C3L1B2 101 A1′L4C3L1B3 102 A1′L4C3L1′B1 103 A1′L4C3L1′B1′ 104A1′L4C3L1′B2 105 A1′L4C3L1′B3 106 A1′L4C3L2B1 107 A1′L4C3L2B1′ 108A1′L4C3L2B2 109 A1′L4C3L2B3 110 A1′L5C1L1B1 111 A1′L5C1L1B1′ 112A1′L5C1L1B2 113 A1′L5C1L1B3 114 A1′L5C1L1′B1 115 A1′L5C1L1′B1′ 116A1′L5C1L1′B2 117 A1′L5C1L1′B3 118 A1′L5C1L2B1 119 A1′L5C1L2B1′ 120A1′L5C1L2B2 121 A1′L5C1L2B3 122 A1′L5C1′L1B1 123 A1′L5C1′L1B1′ 124A1′L5C1′L1B2 125 A1′L5C1′L1B3 126 A1′L5C1′L1′B1 127 A1′L5C1′L1′B1′ 128A2L4C1L1B4 129 A2L4C1L1′B4 130 A2L4C1L2B4 131 A2L4C1′L1B4 132A2L4C1′L1′B4 133 A2L4C1′L2B4 134 A2L4C2L1B4 135 A2L4C2L1′B4 136A2L4C2L2B4 137 A2L4C3L1B4 138 A2L4C3L1′B4 139 A2L4C3L2B4 140 A2L5C1L1B4141 A2L5C1L1′B4 142 A2L5C1L2B4 143 A2L5C1′L1B4 144 A2L5C1′L1′B4 145A2L5C1′L2B4 146 A2L5C2L1B4 147 A2L5C2L1′B4 148 A2L5C2L2B4 149 A2L5C3L1B4150 A2L5C3L1′B4 151 A2L5C3L2B4 152 A1L4C3L1B4 153 A1L4C3L1′B4 154A1L4C3L2B4 155 A1L5C3L1B4 156 A1L5C3L1′B4 157 A1L5C3L2B4 158 A1L4C4L2B1159 A1L4C4L2B1′ 160 A1L4C4L2B2 161 A1L4C4L2B3 162 A1L5C4L2B1 163A1L5C4L2B1′ 164 A1L5C4L2B2 165 A1L5C4L2B3 166 A1′L4C4L2B1 167A1′L4C4L2B1′ 168 A1′L4C4L2B2 169 A1′L4C4L2B3 170 A2L4C4L2B4 171A2L5C4L2B4 172 A1L4C4L2B4 173 A1L5C4L2B4 174 A1L4C4L2′B1 175A1L4C4L2′B1′ 176 A1L4C4L2′B2 177 A1L4C4L2′B3 178 A1L5C4L2′B1 179A1L5C4L2′B1′ 180 A1L5C4L2′B2 181 A1L5C4L2′B3 182 A1′L4C4L2′B1 183A1′L4C4L2′B1′ 184 A1′L4C4L2′B2 185 A1′L4C4L2′B3 186 A2L4C4L2′B4 187A2L5C4L2′B4 188 A1L4C4L2′B4 189 A1L5C4L2′B4 190 A1L4C1L2B1 191A1L4C1L2B1′ 192 A1L4C1L2B2 193 A1L4C1L2B3 194 A1L4C1′L2B1 195A1L4C1′L2B1′ 196 A1L4C1′L2B2 197 A1L4C1′L2B3 198 A1L4C2L2B1 199A1L4C2L2B1′ 200 A1L4C2L2B2 201 A1L4C2L2B3 202 A1L5C1L2B1 203 A1L5C1L2B1′204 A1L5C1L2B2 205 A1L5C1L2B3 206 A1L5C1′L2B1 207 A1L5C1′L2B1′ 208A1L5C1′L2B2 209 A1L5C1′L2B3 210 A1L5C2L2B1 211 A1L5C2L2B1′ 212A1L5C2L2B2 213 A1L5C2L2B3 214 A1′L4C1L2B1 215 A1′L4C1L2B1′ 216A1′L4C1L2B2 217 A1′L4C1L2B3 218 A1′L4C1′L2B1 219 A1′L4C1′L2B1′ 220A1′L4C1′L2B2 221 A1′L4C1′L2B3 222 A1′L4C2L2B1 223 A1′L4C2L2B1′ 224A1′L4C2L2B2 225 A1′L4C2L2B3 226 A1′L5C1L2B1 227 A1′L5C1L2B1′ 228A1′L5C1L2B2 229 A1′L5C1L2B3 230 A2L4C1L2B4 231 A2L4C1′L2B4 232A2L4C2L2B4 233 A2L5C1L2B4 234 A2L5C1′L2B4 235 A2L5C2L2B4 236 A1L4C1L2′B1237 A1L4C1L2′B1′ 238 A1L4C1L2′B2 239 A1L4C1L2′B3 240 A1L4C1′L2′B1 241A1L4C1′L2′B1′ 242 A1L4C1′L2′B2 243 A1L4C1′L2′B3 244 A1L4C2L2′B1 245A1L4C2L2′B1′ 246 A1L4C2L2′B2 247 A1L4C2L2′B3 248 A1L5C1L2′B1 249A1L5C1L2′B1′ 250 A1L5C1L2′B2 251 A1L5C1L2′B3 252 A1L5C1′L2′B1 253A1L5C1′L2′B1′ 254 A1L5C1′L2′B2 255 A1L5C1′L2′B3 256 A1L5C2L2′B1 257A1L5C2L2′B1′ 258 A1L5C2L2′B2 259 A1L5C2L2′B3 260 A1′L4C1L2′B1 261A1′L4C1L2′B1′ 262 A1′L4C1L2′B2 263 A1′L4C1L2′B3 264 A1′L4C1′L2′B1 265A1′L4C1′L2′B1′ 266 A1′L4C1′L2′B2 267 A1′L4C1′L2′B3 268 A1′L4C2L2′B1 269A1′L4C2L2′B1′ 270 A1′L4C2L2′B2 271 A1′L4C2L2′B3 272 A1′L5C1L2′B1 273A1′L5C1L2′B1′ 274 A1′L5C1L2′B2 275 A1′L5C1L2′B3 276 A2L4C1L2′B4 277A2L4C1′L2′B4 278 A2L4C2L2′B4 279 A2L5C1L2′B4 280 A2L5C1′L2′B4 281A2L5C2L2′B4 282 A2L4C4L1B1 283 A2L4C4L1B1′ 284 A2L4C4L1B2 285 A2L4C4L1B3286 A2L4C4L1′B1 287 A2L4C4L1′B1′ 288 A2L4C4L1′B2 289 A2L4C4L1′B3 290A2L5C4L1B1 291 A2L5C4L1B1′ 292 A2L5C4L1B2 293 A2L5C4L1B3 294 A2L5C4L1′B1295 A2L5C4L1′B1′ 296 A2L5C4L1′B2 297 A2L5C4L1′B3 298 A1′L4C4L1B3 299A1′L4C4L1′B3 300 A1′L5C1′L1′B2 301 A1′L5C1′L1′B3 302 A1′L5C1′L2B1 303A1′L5C1′L2B1′ 304 A1′L5C1′L2B2 305 A1′L5C1′L2B3 306 A1′L5C2L1B1 307A1′L5C2L1B1′ 308 A1′L5C2L1B2 309 A1′L5C2L1B3 310 A1′L5C2L1′B1 311A1′L5C2L1′B1′ 312 A1′L5C2L1′B2 313 A1′L5C2L1′B3 314 A1′L5C2L2B1 315A1′L5C2L2B1′ 316 A1′L5C2L2B2 317 A1′L5C2L2B3 318 A1′L5C3L1B1 319A1′L5C3L1B1′ 320 A1′L5C3L1B2 321 A1′L5C3L1B3 322 A1′L5C3L1′B1 323A1′L5C3L1′B1′ 324 A1′L5C3L1′B2 325 A1′L5C3L1′B3 326 A1′L5C3L2B1 327A1′L5C3L2B1′ 328 A1′L5C3L2B2 329 A1′L5C3L2B3 330 A2L4C1L1B1 331A2L4C1L1B1′ 332 A2L4C1L1B2 333 A2L4C1L1B3 334 A2L4C1L1′B1 335A2L4C1L1′B1′ 336 A2L4C1L1′B2 337 A2L4C1L1′B3 338 A2L4C1L2B1 339A2L4C1L2B1′ 340 A2L4C1L2B2 341 A2L4C1L2B3 342 A2L4C1′L1B1 343A2L4C1′L1B1′ 344 A2L4C1′L1B2 345 A2L4C1′L1B3 346 A2L4C1′L1′B1 347A2L4C1′L1′B1′ 348 A2L4C1′L1′B2 349 A2L4C1′L1′B3 350 A2L4C1′L2B1 351A2L4C1′L2B1′ 352 A2L4C1′L2B2 353 A2L4C1′L2B3 354 A2L4C2L1B1 355A2L4C2L1B1′ 356 A2L4C2L1B2 357 A2L4C2L1B3 358 A2L4C2L1′B1 359A2L4C2L1′B1′ 360 A2L4C2L1′B2 361 A2L4C2L1′B3 362 A2L4C2L2B1 363A2L4C2L2B1′ 364 A2L4C2L2B2 365 A2L4C2L2B3 366 A2L4C3L1B1 367 A2L4C3L1B1′368 A2L4C3L1B2 369 A2L4C3L1B3 370 A2L4C3L1′B1 371 A2L4C3L1′B1′ 372A2L4C3L1′B2 373 A2L4C3L1′B3 374 A2L4C3L2B1 375 A2L4C3L2B1′ 376A2L4C3L2B2 377 A2L4C3L2B3 378 A2L5C1L1B1 379 A2L5C1L1B1′ 380 A2L5C1L1B2381 A2L5C1L1B3 382 A2L5C1L1′B1 383 A2L5C1L1′B1′ 384 A2L5C1L1′B2 385A2L5C1L1′B3 386 A2L5C1L2B1 387 A2L5C1L2B1′ 388 A2L5C1L2B2 389 A2L5C1L2B3390 A2L5C1′L1B1 391 A2L5C1′L1B1′ 392 A2L5C1′L1B2 393 A2L5C1′L1B3 394A2L5C1′L1′B1 395 A2L5C1′L1′B1′ 396 A2L5C1′L1′B2 397 A2L5C1′L1′B3 398A2L5C1′L2B1 399 A2L5C1′L2B1′ 400 A2L5C1′L2B2 401 A2L5C1′L2B3 402A2L5C2L1B1 403 A2L5C2L1B1′ 404 A2L5C2L1B2 405 A2L5C2L1B3 406 A2L5C2L1′B1407 A2L5C2L1′B1′ 408 A2L5C2L1′B2 409 A2L5C2L1′B3 410 A2L5C2L2B1 411A2L5C2L2B1′ 412 A2L5C2L2B2 413 A2L5C2L2B3 414 A2L5C3L1B1 415 A2L5C3L1B1′416 A2L5C3L1B2 417 A2L5C3L1B3 418 A2L5C3L1′B1 419 A2L5C3L1′B1′ 420A2L5C3L1′B2 421 A2L5C3L1′B3 422 A2L5C3L2B1 423 A2L5C3L2B1′ 424A2L5C3L2B2 425 A2L5C3L2B3 426 A1′L4C3L1B4 427 A1′L4C3L1′B4 428A1′L4C3L2B4 429 A1′L5C3L1B4 430 A1′L5C3L1′B4 431 A1′L5C3L2B4 432A1L4C1L2B4 433 A1L4C1′L2B4 434 A1L4C2L2B4 435 A1L5C1L2B4 436 A1L5C1′L2B4437 A1L5C2L2B4 438 A1′L4C1L2B4 439 A1′L4C1′L2B4 440 A1′L4C2L2B4 441A1′L5C1L2B4 442 A1′L5C1′L2B4 443 A1′L5C2L2B4 444 A1L5C1L1B4 445A1L5C1L1′B4 446 A1L5C1′L1B4 447 A1L5C1′L1′B4 448 A1L5C2L1B4 449A1L5C2L1′B4 450 A1′L5C1L1B4 451 A1′L5C1L1′B4 452 A1′L5C1′L1B4 453A1′L5C1′L1′B4 454 A1′L5C2L1B4 455 A1′L5C2L1′B4 456 A1′L5C4L2B1 457A1′L5C4L2B1′ 458 A1′L5C4L2B2 459 A1′L5C4L2B3 460 A2L4C4L2B1 461A2L4C4L2B1′ 462 A2L4C4L2B2 463 A2L4C4L2B3 464 A2L5C4L2B1 465 A2L5C4L2B1′466 A2L5C4L2B2 467 A2L5C4L2B3 468 A1′L4C4L2B4 469 A1′L5C4L2B4 470A1′L5C4L2′B1 471 A1′L5C4L2′B1′ 472 A1′L5C4L2′B2 473 A1′L5C4L2′B3 474A2L4C4L2′B1 475 A2L4C4L2′B1′ 476 A2L4C4L2′B2 477 A2L4C4L2′B3 478A2L5C4L2′B1 479 A2L5C4L2′B1′ 480 A2L5C4L2′B2 481 A2L5C4L2′B3 482A1′L4C4L2′B4 483 A1′L5C4L2′B4 484 A1′L5C1′L2B1 485 A1′L5C1′L2B1′ 486A1′L5C1′L2B2 487 A1′L5C1′L2B3 488 A1′L5C2L2B1 489 A1′L5C2L2B1′ 490A1′L5C2L2B2 491 A1′L5C2L2B3 492 A2L4C1L2B1 493 A2L4C1L2B1′ 494A2L4C1L2B2 495 A2L4C1L2B3 496 A2L4C1′L2B1 497 A2L4C1′L2B1′ 498A2L4C1′L2B2 499 A2L4C1′L2B3 500 A2L4C2L2B1 501 A2L4C2L2B1′ 502A2L4C2L2B2 503 A2L4C2L2B3 504 A2L5C1L2B1 505 A2L5C1L2B1′ 506 A2L5C1L2B2507 A2L5C1L2B3 508 A2L5C1′L2B1 509 A2L5C1′L2B1′ 510 A2L5C1′L2B2 511A2L5C1′L2B3 512 A2L5C2L2B1 513 A2L5C2L2B1′ 514 A2L5C2L2B2 515 A2L5C2L2B3516 A1L4C1L2B4 517 A1L4C1′L2B4 518 A1L4C2L2B4 519 A1L5C1L2B4 520A1L5C1′L2B4 521 A1L5C2L2B4 522 A1′L4C1L2B4 523 A1′L4C1′L2B4 524A1′L4C2L2B4 525 A1′L5C1L2B4 526 A1′L5C1′L2B4 527 A1′L5C2L2B4 528A1′L5C1′L2′B1 529 A1′L5C1′L2′B1′ 530 A1′L5C1′L2′B2 531 A1′L5C1′L2′B3 532A1′L5C2L2′B1 533 A1′L5C2L2′B1′ 534 A1′L5C2L2′B2 535 A1′L5C2L2′B3 536A2L4C1L2′B1 537 A2L4C1L2′B1′ 538 A2L4C1L2′B2 539 A2L4C1L2′B3 540A2L4C1′L2′B1 541 A2L4C1′L2′B1′ 542 A2L4C1′L2′B2 543 A2L4C1′L2′B3 544A2L4C2L2′B1 545 A2L4C2L2′B1′ 546 A2L4C2L2′B2 547 A2L4C2L2′B3 548A2L5C1L2′B1 549 A2L5C1L2′B1′ 550 A2L5C1L2′B2 551 A2L5C1L2′B3 552A2L5C1′L2′B1 553 A2L5C1′L2′B1′ 554 A2L5C1′L2′B2 555 A2L5C1′L2′B3 556A2L5C2L2′B1 557 A2L5C2L2′B1′ 558 A2L5C2L2′B2 559 A2L5C2L2′B3 560A1L4C1L2′B4 561 A1L4C1′L2′B4 562 A1L4C2L2′B4 563 A1L5C1L2′B4 564A1L5C1′L2′B4 565 A1L5C2L2′B4 566 A1′L4C1L2′B4 567 A1′L4C1′L2′B4 568A1′L4C2L2′B4 569 A1′L5C1L2′B4 570 A1′L5C1′L2′B4 571 A1′L5C2L2′B4 572A2L4C4L1B4 573 A2L4C4L1′B4 574 A2L5C4L1B4 575 A2L5C4L1′B4 576A1′L5C4L1B1 577 A1′L5C4L1B1′ 578 A1′L5C4L1B2 579 A1′L5C4L1B3 580A1′L5C4L1′B1 581 A1′L5C4L1′B1′ 582 A1′L5C4L1′B2 583 A1′L5C4L1′B3 584A1′L5C4L1B4 585 A1′L5C4L1′B4 586 A1L5C4L1B1 587 A1L5C4L1B1′ 588A1L5C4L1B2 589 A1L5C4L1B3 590 A1L5C4L1′B1 591 A1L5C4L1′B1′ 592A1L5C4L1′B2 593 A1L5C4L1′B3 594 A1L5C4L1B4 595 A1L5C4L1′B4 596A1L4C4L1B3 597 A1L4C4L1′B3

TABLE 2 Formulas of Additional Active Compounds

Formula 598

Formula 599

Formula 600

Formula 601

Formula 602

Formula 603

Formula 604

Formula 605

Formula 606

Formula 607

Formula 608

Formula 609

Formula 610

Formula 611

Formula 612

Formula 613

Formula 614

Formula 615

Formula 616

Formula 617

Formula 618

Formula 619

Formula 620

Formula 621

Formula 622

Formula 623

Formula 624

Formula 625

Formula 626

Formula 627

Formula 628

Formula 629

Formula 630

Formula 631

Formula 632

Formula 633

Formula 634

Formula 635

Formula 636

Formula 637

Formula 638

Formula 639

Formula 640

Formula 641

Formula 642

Formula 643

Formula 644

Formula 645

Formula 646

Formula 647

Formula 648

Formula 649

Formula 650

Formula 651

Formula 652

Formula 653

Formula 654

Additionally, the disclosure includes compounds and salts of Formula I,Formula I′ and Formula I″ and pharmaceutically acceptable compositionsthereof, and any of their subformulae (2-654) in which at least one ofthe following conditions is met in the embodiments described below.

The R¹² and R¹³ Amino Substituents

The invention includes a compound of Formula I, Formula I′ or FormulaI″, a pharmaceutically acceptable salt or composition thereof, whereinat least one of R¹² or R¹³ on the A1 or A2 group is an aminosubstituent, for example, R³².

One of R¹² and R¹³ is selected from R³¹ and the other of R¹² and R¹³ isselected from R³². In another embodiment, each of R¹² and R¹³ can beindependently selected from R³².

R³¹ is selected from hydrogen, halogen, hydroxyl, nitro, cyano, amino,—COOH, C₁-C₂haloalkyl, C₁-C₂haloalkoxy, C₁-C₆alkyl,—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₂-C₆alkenyl, C₂-C₆alkanoyl, C₁-C₆alkoxy,C₂-C₆alkenyloxy, —C(O)OR⁹, C₁-C₆thioalkyl, —C₀-C₄alkyNR⁹R¹⁰,—C(O)NR⁹R¹⁰, —SO₂R⁹, —SO₂NR⁹R¹⁰, —OC(O)R⁹, and —C(NR⁹)NR⁹R¹⁰, each ofwhich R³¹ other than hydrogen, halogen, hydroxyl, nitro, cyano,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy is unsubstituted or substituted withone or more substituents independently selected from halogen, hydroxyl,nitro, cyano, amino, —COOH, —CONH₂ C₁-C₂haloalkyl, and C₁-C₂haloalkoxy,and each of which R³¹ is also optionally substituted with onesubstituent selected from phenyl and 4- to 7-membered heterocyclecontaining 1, 2, or 3 heteroatoms independently selected from N, O, andS; which phenyl or 4- to 7-membered heterocycle is unsubstituted orsubstituted with one or more substituents independently selected fromhalogen, hydroxyl, nitro, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkanoyl, C₁-C₆alkoxy, (mono- and di-C₁-C₆alkylamino)C₀-C₄alkyl,C₁-C₆alkylester, —C₀-C₄alkyl)(C₃-C₇cycloalkyl), C₁-C₂haloalkyl, andC₁-C₂haloalkoxy;

R³² is selected from NR⁷²R⁷³, NR⁹SO₂R⁷³, or N(SO₂R⁹)CH₂C(O)R⁷⁴.

In certain embodiments, R³² is selected from a moiety in FIG. 15

Non-Limiting R²/R¹ Embodiments

In one embodiment, R¹² is NR⁷²R⁷³.

In one embodiment, R¹² is NR⁹SO₂R⁷³.

In one embodiment, R¹² is N(SO₂R⁹)CH₂C(O)R⁷⁴.

In one embodiment, R₁₃ is hydrogen

In one embodiment, R¹³ is NR⁷²R⁷³.

In one embodiment, R¹³ is NR⁹SO₂R⁷³.

In one embodiment, R¹³ is N(SO₂R⁹)CH₂C(O)R⁷⁴.

In one embodiment, R⁷² is aryl.

In one embodiment, R⁷² is heteroaryl.

In one embodiment, R⁷² is hetercycle.

In one embodiment, R⁷² is selected from alkynyl, hydroxyl andC₁-C₆alkoxy.

In one embodiment, R⁷² is (C₃-C₇cycloalkyl)C₀-C₄alkyl or(aryl)C₀-C₄alkyl.

In one embodiment, R⁷² is (heterocycle)C₀-C₄alkyl or(heteroaryl)C₀-C₄alkyl.

In one embodiment, R⁷² is —C₁-C₄alkylOC(O)OC₁-C₆alkyl or—C₁-C₄alkylOC(O)C₁-C₆alkyl

In one embodiment, R⁷² is —C₁-C₄alkyC(O)OC₁-C₆alkyl.

In one embodiment, R⁷² is selected from —S(O)(O)(alkyl), —S(O)(alkyl),—S(O)(O)(heteroalkyl), —S(O)(heteroalkyl), —S(O)(O)(aryl), —S(O)(aryl),—S(O)(O)(heteroaryl) and —S(O)(heteroaryl).

In one embodiment, R⁷³ is hydroxyl.

In one embodiment, R⁷³ is selected from cyano and amino.

In one embodiment, R⁷³ is selected from C₁-C₆alkyl, C₁-C₆haloalkyl andC₁-C₆alkoxy.

In one embodiment, R⁷³ is (C₃-C₇cycloalkyl)C₀-C₄alkyl,(phenyl)C₀-C₄alkyl, or —C₁-C₄alkylOC(O)OC₁-C₆alkyl.

In one embodiment, R⁷³ is —C₁-C₄alkylOC(O)C₁-C₆alkyl,—C₁-C₄alkyC(O)OC₁-C₆alkyl,

In one embodiment, the disclosure provides compounds of Formula I,wherein; one of R¹² and R¹³ is H and the other of R¹² and R¹³ is R³²,where

R³² is selected from NR⁷²R⁷³, NR⁹SO₂R⁷³, or N(SO₂R⁹)CH₂C(O)R⁷⁴, each ofwhich is optionally substituted;

wherein R⁹, R⁷², R⁷³, and R⁷⁴ are as defined in the summary sectionabove.

In another embodiment, the disclosure provides compounds of Formula I,wherein;

R¹, R¹′, R², and R^(3′) are all hydrogen;

R² is fluoro and R³ is hydrogen, —C₀-C₄alkyl(C₃-C₇cycloalkyl), or—O—C₀-C₄alkyl(C₃-C₇cycloalkyl);

R⁵ is hydrogen, halogen, or C₁-C₂alkyl;

R¹¹, R¹³, R¹⁴, and R¹⁵ if present, are independently selected at eachoccurrence from hydrogen, halogen, hydroxyl, amino, C₁-C₄alkyl,C₁-C₄alkoxy, —C₀-C₂alkyl(mono- and di-C₁-C₂alkylamino), trifluoromethyl,and trifluoromethoxy;

X¹² is CR¹²; and

R¹² is selected from NR⁷²R⁷³, NR⁹SO₂R⁷³, or N(SO₂R⁹)CH₂C(O)R⁷⁴, each ofwhich is optionally substituted;

wherein R⁹, R⁷², R⁷³, and R⁷⁴ are as defined in the summary sectionabove.

In one embodiment, the disclosure provides compounds of Formula I,wherein;

m is 0 or 1;

R² is halogen, R^(2′) is hydrogen or halogen, and R³ is hydrogen,halogen, —C₀-C₄alkyl(C₃-C₇cycloalkyl), or—O—C₀-C₄alkyl(C₃-C₇cycloalkyl);

R⁶ is —C(O)C₁-C₄alkyl, —C(O)NH₂, —C(O)CF₃, —C(O)(C₃-C₇cycloalkyl), or-ethyl(cyanoimino);

one of R¹² and R¹³ is selected from hydrogen, halogen, C₁-C₄alkyl,C₁-C₄alkoxy, trifluoromethyl, and trifluoromethoxy; the other of R¹² andR¹³ is R³², where

R³² is selected from NR⁷²R⁷³, NR⁹SO₂R⁷³, or N(SO₂R⁹)CH₂C(O)R⁷⁴, whichcan be optionally substituted;

wherein R⁹, R⁷², R⁷³, and R⁷⁴ are as defined in the summary sectionabove.

In one embodiment, the disclosure provides compounds of Formula I,wherein;

one of R¹² and R¹³ is hydrogen, hydroxyl, halogen, methyl, or methoxy;and the other of R¹² and R¹³ is R³², where

R³² is selected from NR⁷²R⁷³, NR⁹SO₂R⁷³, or N(SO₂R⁹)CH₂C(O)R⁷⁴, each ofwhich is optionally substituted;

wherein R⁹, R⁷², R⁷³, and R⁷⁴ are as defined in the summary sectionabove.

In one embodiment, R³² may be unsubstituted or substituted with one ormore substituents independently selected from halogen, hydroxyl, nitro,cyano, amino, oxo, —B(OH)₂, —Si(CH₃)₃, —COOH, —CONH₂, —P(O)(OH)₂,C₁-C₆alkyl, C₁-C₆alkoxy, —C₀-C₂alkyl(mono- and di-C₁-C₄alkylamino),C₁-C₆alkylester, C₁-C₄alkylamino, C₁-C₄hydroxylalkyl, C₁-C₂haloalkyl,and C₁-C₂haloalkoxy.

Central Core Moiety

The central core moiety, C, in Formula I is described below.

C is C1, C1′, C2, C3 or C4.

C1, C1′, C2, C3 and C4 are described in the summary section.

Non-Limiting Central Core Embodiments

In certain embodiments, R¹ and R^(1′) or R³ and R^(3′) may be takentogether to form a 3- to 6-membered carbocyclic spiro ring or a 3- to6-membered heterocyclic spiro ring containing 1 or 2 heteroatomsindependently selected from N, O, or S; R² and R^(2′) may be takentogether to form a 3- to 6-membered carbocyclic spiro ring; or R² andR^(2′) may be taken together to form a 3- to 6-membered heterocyclicspiro ring; each of which ring may be unsubstituted or substituted with1 or more substituents independently selected from halogen (and inparticular F), hydroxyl, cyano, —COOH, C₁-C₄alkyl (including inparticular methyl), C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, hydroxyC₁-C₄alkyl, (mono- anddi-C₁-C₄alkylamino)C₀-C₄alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl),—O—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

In other embodiments, R¹ and R² may be taken together to form a3-membered carbocyclic ring; R¹ and R² may be taken together to form a4, 5 or 6-membered carbocyclic or aryl ring or a 4, 5 or 6 memberedheterocyclic or heteroaryl ring containing 1 or 2 heteroatomsindependently selected from N, O, and S; or R² and R³, if bound toadjacent carbon atoms, may be taken together to form a 3- to 6-memberedcarbocyclic or aryl ring or a 3- to 6-membered heterocyclic orheteroaryl ring; each of which ring may be unsubstituted or substitutedwith 1 or more substituents independently selected from halogen (and inparticular F), hydroxyl, cyano, —COOH, C₁-C₄alkyl (including inparticular methyl), C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₂-C₄alkanoyl, hydroxyC₁-C₄alkyl, (mono- anddi-C₁-C₄alkylamino)C₀-C₄alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl),—O—C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

In one embodiment, the central core moiety is proline.

In one embodiment, the central core moiety is 4-fluoroproline.

In one embodiment, R¹, R^(1′), R^(2′), R³, and R^(3′), if present, areall hydrogen; and R² is fluoro.

In one embodiment, R¹, R^(1′), R^(2′), and R^(3′), if present, are allhydrogen; and R² is fluoro and R³ is —C₀-C₄alkyl(C₃-C₇cycloalkyl) or—C₀-C₄alkyl(C₃-C₇cycloalkyl).

In one embodiment, R¹ and R² are taken together to form a 3- to6-membered cycloalkyl group, and R^(1′), R^(2′), R³, and R^(3′), wherepresent, are all hydrogen. In one embodiment, the bicycle is fused in acis fashion. In one embodiment, the bicyclic ring is fused in a transfashion.

In one embodiment, R¹ and R² are taken together to form a 3- to6-membered cycloalkyl group that is cis with respect to the carboxylgroup of L-proline as shown below:

In one embodiment, R¹ and R² are taken together to form a 3- to6-membered cycloalkyl group that is trans with respect to the carboxylgroup of L-proline as shown below:

In one embodiment, R¹, R^(1′), R³, and R^(3′), if present, are allhydrogen, and R² and R^(2′) are taken together to form a 5- or6-membered heterocycloalkyl group having 1 or 2 oxygen atoms.

In one embodiment, R¹ is hydrogen and R² is fluoro.

In one embodiment, R¹ and R² are joined to form a 3 membered ring.

In one embodiment, R¹ and R² are taken together to form a 3-memberedcycloalkyl group that is cis with respect to the carboxyl group ofL-proline as shown below:

In one embodiment, R¹ and R² are taken together to form a 3-memberedcycloalkyl group that is trans with respect to the carboxyl group ofL-proline as shown below:

In one embodiment, R² and R³ are taken together to form a 3- to6-membered cycloalkyl group, and R¹, R^(1′), R^(2′) and R^(3′), wherepresent, are selected from hydrogen, C₁-C₃ alkyl or C₁-C₃ alkoxy.

In one embodiment, R² and R³ are taken together to form a 3- to6-membered cycloalkyl group that is cis with respect to the carboxylgroup of L-proline as shown below:

In one embodiment, R² and R³ are taken together to form a 3- to6-membered cycloalkyl group that is trans with respect to the carboxylgroup of L-proline as shown below:

In one embodiment, R² and R³ are taken together to form a 3-memberedcycloalkyl group that is cis with respect to the carboxyl group ofL-proline as shown below:

In one embodiment, R² and R³ are taken together to form a 3-memberedcycloalkyl group that is trans with respect to the carboxyl group ofL-proline as shown below:

In one embodiment, R¹, R^(1′), R³, and R^(3′), if present, are allhydrogen, and R² and R^(2′) are taken together to form a 5- or6-membered heterocycloalkyl group having 1 or 2 oxygen atoms.

In one embodiment, R¹ is hydrogen and R² is fluoro.

In one embodiment, R¹ and R² are joined to form a 3 membered ring.

The disclosure includes compounds of Formula I in which the centralpyrrolidine is vinyl substituted, for example:

In one embodiment, the compound of Formula I has the structure:

In one embodiment, the central pyrrolidine is modified by addition of asecond heteroatom to a pyrrolidine ring, such as N, O, S, or Si, forexample:

Another modification within the scope of the disclosure is joining asubstituent on the central pyrrolidine ring to R⁷ or R⁸ to form as 5- to6-membered heterocyclic ring, for example:

Example compounds having the modifications disclosed above include:

Central Core L-B Substituents

Illustrative central core L substituents and B substituents in Formula Iare described below.

L is selected from L1, L1′ and L2.

L1 is a bond or is selected from the formulas:

where R¹⁷ is hydrogen, C₁-C₆alkyl, or —C₀-C₄alkyl(C₃-C₇cycloalkyl) andR¹⁸ and R^(18′) are independently selected from hydrogen, halogen,hydroxymethyl, and methyl; and m is 0, 1, 2, or 3.

L2 is described in the summary section.

B is selected from B1, B1′, B2, B3 and B4 which are described in thesummary section.

In one embodiment, -L1-B1- is

whereR²⁶ and R²⁷ are independently selected from hydrogen, halogen, hydroxyl,nitro, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkanoyl, C₁-C₆alkoxy,C₁-C₆thioalkyl, —C₀-C₄alkyl(mono- and di-C₁-C₆alkylamino),—C₀-C₄alkyl(C₃-C₇cycloalkyl), —C₀-C₄alkoxy(C₃-C₇cycloalkyl),C₁-C₂haloalkyl, C₁-C₂haloalkoxy, and C₁-C₂haloalkylthio.

Non-Limiting L-B Embodiments

In one embodiment, -L1-B1- is:

wherein

R¹⁸ and R^(18′) are independently selected from hydrogen, halogen,hydroxymethyl, and methyl; and m is 0 or 1; and

R²⁶, R²⁷, and R²⁸ are independently selected from hydrogen, halogen,hydroxyl, nitro, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkanoyl,C₁-C₆alkoxy, C₁-C₆thioalkyl, (mono- and di-C₁-C₆alkylamino)C₀-C₄alkyl,(C₃-C₇cycloalkyl)C₀-C₄alkyl, (aryl)C₀-C₄alkyl-, (heteroaryl)C₀-C₄alkyl-,and —C₀-C₄alkoxy(C₃-C₇cycloalkyl); each of which R²⁶, R²⁷, and R²⁸ otherthan hydrogen, halogen, hydroxyl, nitro, cyano, is unsubstituted orsubstituted with one or more substituents independently selected fromhalogen, hydroxyl, amino, C₁-C₂alkoxy, C₁-C₂haloalkyl,(C₃-C₇cycloalkyl)C₀-C₄alkyl-, and C₁-C₂haloalkoxy; and

R²⁹ is hydrogen, C₁-C₂alkyl, C₁-C₂haloalkyl or —Si(CH₃)₂C(CH₃)₃.

In one embodiment, -L-B1- moiety is selected:

In one embodiment, -L1-B1- moiety is selected:

In one embodiment, -L2-B1- moiety is selected:

In one embodiment, -L2′-B1- moiety is selected:

In one embodiment, m is 0.

In one embodiment, the disclosure further includes compounds and saltsof Formula I in which B1 is 2-fluoro-3-chlorophenyl. In anotherembodiment, another carbocyclic, aryl, heterocyclic, or heteroaryl groupsuch as 2-bromo-pyridin-6-yl, 1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl,2,2-dichlorocyclopropylmethyl, or 2-fluoro-3-trimethylsilylphenyl isused.

In another embodiment, B1 is phenyl, pyridyl, or indanyl each of whichis unsubstituted or substituted with one or more substituentsindependently selected from hydrogen, halogen, hydroxyl, nitro, cyano,C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkanoyl, C₁-C₆alkoxy, C₁-C₆thioalkyl,(mono- and di-C₁-C₆alkylamino)C₀-C₄alkyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl,—C₀-C₄alkoxy(C₃-C₇cycloalkyl), (phenyl)C₀-C₂alkyl, (pyridyl)C₀-C₂alkyl;each of which substituents other than hydrogen, halogen, hydroxyl,nitro, cyano, is unsubstituted or substituted with one or moresubstituents independently selected from halogen, hydroxyl, amino,C₁-C₂alkyl, C₁-C₂alkoxy, —OSi(CH₃)₂C(CH₃)₃, —Si(CH₃)₂C(CH₃)₃,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

In another embodiment, B1 is phenyl or pyridyl substituted with 1, 2, or3 substituents selected from chloro, bromo, hydroxyl, —SCF₃, C₁-C₂alkyl,C₁-C₂alkoxy, trifluoromethyl, phenyl and trifluoromethoxy each of whichsubstituents other than chloro, bromo, hydroxyl, —SCF₃, can beoptionally substituted.

In certain embodiments, B1 is a 2-fluoro-3-chlorophenyl or a2-fluoro-3-trifluoromethoxyphenyl group.

In one embodiment, B1 is pyridyl, optionally substituted with halogen,C₁-C₂alkoxy, and trifluoromethyl.

In one embodiment, B1 is phenyl, substituted with 1, 2, or 3substituents independently selected from halogen, C₁-C₂alkyl,C₁-C₂alkoxy, trifluoromethyl, and optionally substituted phenyl.

In one embodiment, R²³ is independently selected at each occurrence from(C₃-C₇cycloalkyl)C₀-C₄alkyl, (phenyl)C₀-C₄alkyl, (4- to 7-memberedheterocycloalkyl)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S, and (5- or 6-membered unsaturated or aromaticheterocycle)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S.

In one embodiment, L1-B3 is:

R^(27′), and R^(28′) are independently selected from hydrogen, fluoro,bromo, iodo, hydroxyl, nitro, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkanoyl, C₂-C₆alkoxy, C₂-C₆thioalkyl, (mono- anddi-C₁-C₆alkylamino)C₀-C₄alkyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl,(aryl)C₀-C₄alkyl-, (heteroaryl)C₀-C₄alkyl-, and—C₀-C₄alkoxy(C₃-C₇cycloalkyl); each of which R^(27′), and R^(28′) otherthan hydrogen, fluoro, bromo, iodo, hydroxyl, nitro, and cyano, isunsubstituted or substituted with one or more substituents independentlyselected from halogen, hydroxyl, amino, C₁-C₂alkoxy, C₁-C₂haloalkyl,(C₃-C₇cycloalkyl)C₀-C₄alkyl-, and C₁-C₂haloalkoxy.

Central Core (L3)-A Substituent

The central core (L3)-A substituent in Formula I is described below.

L3 is selected from L4 and L5;

L4 is —C(O)—.

L5 is described above in the summary section.

A is selected from A1, A1′ and A2.

A1, A1′ and A2 are described above in the summary section.

In one embodiment, R⁵ and R⁶ are independently selected from —CHO,—C(O)NH₂, —C(O)NH(CH₃), C₂-C₆alkanoyl, and hydrogen.

In one embodiment, each R⁵ and R⁶ other than hydrogen, hydroxyl, cyano,and —COOH is unsubstituted or substituted with one or more substituentsindependently selected from halogen, hydroxyl, amino, imino, cyano,cyanoimino, C₁-C₂alkyl, C₁-C₄alkoxy, —C₀-C₂alkyl(mono- anddi-C₁-C₄alkylamino), C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

In one embodiment, R⁸ and R^(8′) are independently hydrogen or methyl.

In one embodiment, R⁸ and R^(8′) are hydrogen.

In one embodiment, R⁷ is hydrogen or methyl.

In one embodiment, R⁷ is hydrogen.

Embodiments of Formulas IA, IB, IC, and ID

To further illustrate the invention, various embodiments of Formula IA,IB, IC and ID are provided. These are presented by way of example toshow some of the variations among presented compounds within theinvention and can be applied to any of the Formulas herein, and are notintended to limit the invention.

In one aspect, this disclosure includes compounds and salts of FormulaIA:

whereR⁶, R¹³, and B3 may carry any of the definitions set forth herein forthis variable.

In another aspect, this disclosure includes compounds and salts ofFormula IB, IC, and ID.

In Formulas IA, IB, IC, and ID, the variables may include any of thedefinitions set forth herein that results in a stable compound. Incertain embodiments, the following conditions apply for Formula IB andIC.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=0, R¹ is H, R² is F, R⁶ is alkanoyl, R¹² is NR⁷²R⁷³, R¹³is H, R⁷² is H, R⁷³ is heteroaryl, and B is heteroaryl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=0, R¹ and R² are joined to form a 3 membered ring, R⁶ isalkanoyl, R¹² is NR⁷²R⁷³, R¹³ is H, R⁷² is H, R⁷³ is heteroaryl, and Bis heteroaryl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=0, R¹ is H, R² is F, R⁶ is amide, R¹² is NR⁷²R⁷³, R¹³ isH, R⁷² is H, R⁷³ is heteroaryl, and B is heteroaryl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=0, R¹ and R² are joined to form a 3 membered ring, R⁶ isamide, R¹² is NR⁷²R⁷³, R¹³ is H, R⁷² is H, R⁷³ is heteroaryl, and B isheteroaryl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=0, R¹ is H, R² is F, R⁶ is alkanoyl, R¹² is H, R¹³ isNR⁷²R⁷³, R⁷² is H, R⁷³ is heteroaryl, and B is heteroaryl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=0, R¹ and R² are joined to form a 3 membered ring, R⁶ isalkanoyl, R¹² is H, R¹³ is NR⁷²R⁷³, R⁷² is H, R⁷³ is heteroaryl, and Bis heteroaryl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=0, R¹ is H, R² is F, R⁶ is amide, R¹² is H, R¹³ isNR⁷²R⁷³, R⁷² is H, R⁷³ is heteroaryl, and B is heteroaryl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=0, R¹ and R² are joined to form a 3 membered ring, R⁶ isamide, R¹² is H, R¹³ is NR⁷²R⁷³, R⁷² is H, R⁷³ is heteroaryl, and B isheteroaryl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=0, R¹ is H, R² is F, R⁶ is alkanoyl, R¹² is NR⁷²R⁷³, R¹³is H, R⁷² is H, R⁷³ is heteroaryl, and B is phenyl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=0, R¹ and R² are joined to form a 3 membered ring, R⁶ isalkanoyl, R¹² is NR⁷²R⁷³, R¹³ is H, R⁷² is H, R⁷³ is heteroaryl, and Bis phenyl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=0, R¹ is H, R² is F, R⁶ is amide, R¹² is NR⁷²R⁷³, R¹³ isH, R⁷² is H, R⁷³ is heteroaryl, and B is phenyl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=0, R¹ and R² are joined to form a 3 membered ring, R⁶ isamide, R¹² is NR⁷²R⁷³, R¹³ is H, R⁷² is H, R⁷³ is heteroaryl, and B isphenyl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=0, R¹ is H, R² is F, R⁶ is alkanoyl, R¹² is H, R¹³ isNR²R⁷³, R⁷² is H, R⁷³ is heteroaryl, and B is phenyl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=0, R¹ and R² are joined to form a 3 membered ring, R⁶ isalkanoyl, R¹² is H, R¹³ is NR⁷²R⁷³, R⁷² is H, R⁷³ is heteroaryl, and Bis phenyl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=0, R¹ is H, R² is F, R⁶ is amide, R¹² is H, R¹³ isNR⁷²R⁷³, R⁷² is H, R⁷³ is heteroaryl, and B is phenyl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=0, R¹ and R² are joined to form a 3 membered ring, R⁶ isamide, R¹² is H, R¹³ is NR⁷²R⁷³, R⁷² is H, R⁷³ is heteroaryl, and B isphenyl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=1, R¹ is H, R² is F, R⁶ is alkanoyl, R¹² is NR²R³, R¹³ isH, R⁷² is H, R⁷³ is heteroaryl, and B is heteroaryl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=1, R¹ and R² are joined to form a 3 membered ring, R⁶ isalkanoyl, R¹² is NR⁷²R⁷³, R¹³ is H, R⁷² is H, R⁷³ is heteroaryl, and Bis heteroaryl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=1, R¹ is H, R² is F, R⁶ is amide, R¹² is NR⁷²R⁷³, R¹³ isH, R⁷² is H, R⁷³ is heteroaryl, and B is heteroaryl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=1, R¹ and R² are joined to form a 3 membered ring, R⁶ isamide, R¹² is NR⁷²R⁷³, R¹³ is H, R⁷² is H, R⁷³ is heteroaryl, and B isheteroaryl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=1, R¹ is H, R² is F, R⁶ is alkanoyl, R¹² is H, R¹³ isNR⁷²R⁷³, R⁷² is H, R⁷³ is heteroaryl, and B is heteroaryl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=1, R¹ and R² are joined to form a 3 membered ring, R⁶ isalkanoyl, R¹² is H, R¹³ is NR⁷²R⁷³, R⁷² is H, R⁷³ is heteroaryl, and Bis heteroaryl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=1, R¹ is H, R² is F, R⁶ is amide, R¹² is H, R¹³ isNR⁷²R⁷³, R⁷² is H, R⁷³ is heteroaryl, and B is heteroaryl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=1, R¹ and R² are joined to form a 3 membered ring, R⁶ isamide, R¹² is H, R¹³ is NR⁷²R⁷³, R⁷² is H, R⁷³ is heteroaryl, and B isheteroaryl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=1, R¹ is H, R² is F, R⁶ is alkanoyl, R¹² is NR⁷²R⁷³, R¹³is H, R⁷² is H, R⁷³ is heteroaryl, and B is phenyl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=1, R¹ and R² are joined to form a 3 membered ring, R⁶ isalkanoyl, R¹² is NR⁷²R⁷³, R¹³ is H, R⁷² is H, R⁷³ is heteroaryl, and Bis phenyl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=1, R¹ is H, R² is F, R⁶ is amide, R¹² is NR⁷²R⁷³, R¹³ isH, R⁷² is H, R⁷³ is heteroaryl, and B is phenyl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=1, R¹ and R² are joined to form a 3 membered ring, R⁶ isamide, R¹² is NR⁷²R⁷³, R¹³ is H, R⁷² is H, R⁷³ is heteroaryl, and B isphenyl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=1, R¹ is H, R² is F, R⁶ is alkanoyl, R¹² is H, R¹³ isNR⁷²R⁷³, R⁷² is H, R⁷³ is heteroaryl, and B is phenyl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=1, R¹ and R² are joined to form a 3 membered ring, R⁶ isalkanoyl, R¹² is H, R¹³ is NR⁷²R⁷³, R⁷² is H, R⁷³ is heteroaryl, and Bis phenyl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=1, R¹ is H, R² is F, R⁶ is amide, R¹² is H, R¹³ isNR⁷²R⁷³, R⁷² is H, R⁷³ is heteroaryl, and B is phenyl.

In some embodiments, structures are provided including Formulas IB andIC, wherein m=1, R¹ and R² are joined to form a 3 membered ring, R⁶ isamide, R¹² is H, R¹³ is NR⁷²R⁷³, R⁷² is H, R⁷³ is heteroaryl, and B isphenyl.

Embodiments of Formula 606

To further illustrate the invention, various embodiments of Formula 606are disclosed. In one aspect, the disclosure includes compounds andsalts of Formula 606:

wherein:

R¹, R^(1′), R², R^(2′), R³, and R^(3′) are independently selected fromhydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkoxy, —C₀-C₂alkylNR⁹R¹⁰,—C₀-C₄alkyl(C₃-C₇cycloalkyl), —O—C₀-C₄alkyl(C₃-C₇cycloalkyl),C₁-C₂haloalkyl, and C₁-C₂haloalkoxy;

R⁸ and R^(8′) are independently selected from hydrogen, halogen, andmethyl;

R⁵ is hydrogen, hydroxyl, cyano, —COOH, C₁-C₆alkyl, C₁-C₆alkoxy,C₂-C₆alkanoyl —C₀-C₄alkyl(C₃-C₇cycloalkyl),—C(O)C₀-C₄alkyl(C₃-C₇cycloalkyl, C₁-C₂haloalkyl, or C₁-C₂haloalkoxy);

R⁶ is —C(O)CH₃, —C(O)NH₂, —C(O)CF₃, —C(O)(cyclopropyl), or-ethyl(cyanoimino); and

R¹¹ and R¹⁴ are independently selected from hydrogen, halogen, hydroxyl,amino, nitro, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkanoyl,C₁-C₆alkoxy, C₁-C₆thioalkyl, —C₀-C₄alkyl(mono- and di-C₁-C₆alkylamino),—C₀-C₄alkyl(C₃-C₇cycloalkyl), —OC₀-C₄alkyl(C₃-C₇cycloalkyl),C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

Prodrugs of Formula I, Formula I′ and Formula I″ are also within thescope of the disclosure.

III. Pharmaceutical Preparations

Active compounds described herein can be administered to a host in needthereof as the neat chemical, but are more typically administered as apharmaceutical composition that includes an effective amount for a host,typically a human, in need of such treatment of an active compound asdescribed herein or its pharmaceutically acceptable salt. Thus, in oneembodiment, the disclosure provides pharmaceutical compositionscomprising an effective amount of compound or pharmaceuticallyacceptable salt together with at least one pharmaceutically acceptablecarrier for any of the uses described herein. The pharmaceuticalcomposition may contain a compound or salt as the only active agent, or,in an alternative embodiment, the compound and at least one additionalactive agent.

An effective amount of an active compound as described herein, or theactive compound described herein in combination or alternation with, orpreceded by, concomitant with or followed by another active agent, canbe used in an amount sufficient to (a) inhibit the progression of adisorder mediated by the complement pathway, including an inflammatory,immune, including an autoimmune, disorder or complement Factor D relateddisorder; (b) cause a regression of an inflammatory, immune, includingan autoimmune, disorder or complement Factor D related disorder; (c)cause a cure of an inflammatory, immune, including an autoimmune,disorder or complement Factor D related disorder; or inhibit or preventthe development of an inflammatory, immune, including an autoimmune,disorder or complement Factor D related disorder. Accordingly, aneffective amount of an active compound or its salt or compositiondescribed herein will provide a sufficient amount of the active agentwhen administered to a patient to provide a clinical benefit.

The exact amount of the active compound or pharmaceutical compositiondescribed herein to be delivered to the host, typically a human, in needthereof, will be determined by the health care provider to achieve thedesired clinical benefit.

In certain embodiments the pharmaceutical composition is in a dosageform that contains from about 0.1 mg to about 2000 mg, from about 10 mgto about 1000 mg, from about 100 mg to about 800 mg, or from about 200mg to about 600 mg of the active compound and optionally from about 0.1mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100mg to about 800 mg, or from about 200 mg to about 600 mg of anadditional active agent in a unit dosage form. Examples are dosage formswith at least about 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, 750,800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, or 1700 mg of activecompound, or its salt. In one embodiment, the dosage form has at leastabout 100 mg, 200 mg, 400 mg, 500 mg, 600 mg, 1000 mg, 1200 mg, or 1600mg of active compound, or its salt. The amount of active compound in thedosage form is calculated without reference to the salt. The dosage formcan be administered, for example, once a day (q.d.), twice a day(b.i.d.), three times a day (t.i.d.), four times a day (q.i.d.), onceevery other day (Q2d), once every third day (Q3d), as needed, or anydosage schedule that provides treatment of a disorder described herein.

The pharmaceutical composition may for example include a molar ratio ofthe active compound and an additional active agent that achieves thedesired result. For example, the pharmaceutical composition may containa molar ratio of about 0.5:1, about 1:1, about 2:1, about 3:1 or fromabout 1.5:1 to about 4:1 of an additional active agent in combinationwith the active compound (additional active agent: active compound), orits salt, described herein. In one embodiment, the additional activeagent is an anti-inflammatory or immunosuppressing agent.

Compounds disclosed herein or used as described herein may beadministered orally, topically, parenterally, by inhalation or spray,sublingually, via implant, including ocular implant, transdermally, viabuccal administration, rectally, as an ophthalmic solution, injection,including ocular injection, intraveneous, intra-aortal, intracranial,subdermal, intraperitioneal, subcutaneous, transnasal, sublingual,intrathecal, or rectal or by other means, in dosage unit formulationscontaining conventional pharmaceutically acceptable carriers. For oculardelivery, the compound can be administered, as desired, for example, asa solution, suspension, or other formulation via intravitreal,intrastromal, intracameral, sub-tenon, sub-retinal, retro-bulbar,peribulbar, suprachorodial, subchorodial, chorodial, conjunctival,subconjunctival, episcleral, periocular, transscleral, retrobulbar,posterior juxtascleral, circumcorneal, or tear duct injections, orthrough a mucus, mucin, or a mucosal barrier, in an immediate orcontrolled release fashion or via an ocular device, injection, ortopically administered formulation, for example a solution or suspensionprovided as an eye drop.

The pharmaceutical composition may be formulated as any pharmaceuticallyuseful form, e.g., as an aerosol, a cream, a gel, a gel cap, a pill, amicroparticle, a nanoparticle, an injection or infusion solution, acapsule, a tablet, a syrup, a transdermal patch, a subcutaneous patch, adry powder, an inhalation formulation, in a medical device, suppository,buccal, or sublingual formulation, parenteral formulation, or anophthalmic solution or suspension. Some dosage forms, such as tabletsand capsules, are subdivided into suitably sized unit doses containingappropriate quantities of the active components, e.g., an effectiveamount to achieve the desired purpose.

Pharmaceutical compositions, and methods of manufacturing suchcompositions, suitable for administration as contemplated herein areknown in the art. Examples of known techniques include, for example,U.S. Pat. Nos. 4,983,593, 5,013,557, 5,456,923, 5,576,025, 5,723,269,5,858,411, 6,254,889, 6,303,148, 6,395,302, 6,497,903, 7,060,296,7,078,057, 7,404,828, 8,202,912, 8,257,741, 8,263,128, 8,337,899,8,431,159, 9,028,870, 9,060,938, 9,211,261, 9,265,731, 9,358,478, and9,387,252, incorporated by reference herein.

The pharmaceutical compositions contemplated here can optionally includea carrier. Carriers must be of sufficiently high purity and sufficientlylow toxicity to render them suitable for administration to the patientbeing treated. The carrier can be inert or it can possess pharmaceuticalbenefits of its own. The amount of carrier employed in conjunction withthe compound is sufficient to provide a practical quantity of materialfor administration per unit dose of the compound. Classes of carriersinclude, but are not limited to binders, buffering agents, coloringagents, diluents, disintegrants, emulsifiers, fillers, flavorants,glidents, lubricants, pH modifiers, preservatives, stabilizers,surfactants, solubilizers, tableting agents, and wetting agents. Somecarriers may be listed in more than one class, for example vegetable oilmay be used as a lubricant in some formulations and a diluent in others.Exemplary pharmaceutically acceptable carriers include sugars, starches,celluloses, powdered tragacanth, malt, gelatin; talc, and vegetableoils. Examples of other matrix materials, fillers, or diluents includelactose, mannitol, xylitol, microcrystalline cellulose, calciumdiphosphate, and starch. Examples of surface active agents includesodium lauryl sulfate and polysorbate 80. Examples of drug complexingagents or solubilizers include the polyethylene glycols, caffeine,xanthene, gentisic acid and cylodextrins. Examples of disintegrantsinclude sodium starch gycolate, sodium alginate, carboxymethyl cellulosesodium, methyl cellulose, colloidal silicon dioxide, and croscarmellosesodium. Examples of binders include methyl cellulose, microcrystallinecellulose, starch, and gums such as guar gum, and tragacanth. Examplesof lubricants include magnesium stearate and calcium stearate. Examplesof pH modifiers include acids such as citric acid, acetic acid, ascorbicacid, lactic acid, aspartic acid, succinic acid, phosphoric acid, andthe like; bases such as sodium acetate, potassium acetate, calciumoxide, magnesium oxide, trisodium phosphate, sodium hydroxide, calciumhydroxide, aluminum hydroxide, and the like, and buffers generallycomprising mixtures of acids and the salts of said acids. Optional otheractive agents may be included in a pharmaceutical composition, which donot substantially interfere with the activity of the compound of thepresent invention.

In certain embodiments, the pharmaceutical composition foradministration further includes a compound or salt of Formula I, I′, orI″ and optionally comprises one or more of a phosphoglyceride;phosphatidylcholine; dipalmitoyl phosphatidylcholine (DPPC);dioleylphosphatidyl ethanolamine (DOPE);dioleyloxypropyltriethylammonium (DOTMA); dioleoylphosphatidylcholine;cholesterol; cholesterol ester; diacylglycerol; diacylglycerolsuccinate;diphosphatidyl glycerol (DPPG); hexanedecanol; fatty alcohol such aspolyethylene glycol (PEG); polyoxyethylene-9-lauryl ether; a surfaceactive fatty acid, such as palmitic acid or oleic acid; fatty acid;fatty acid monoglyceride; fatty acid diglyceride; fatty acid amide;sorbitan trioleate (Span®85) glycocholate; sorbitan monolaurate(Span®20); polysorbate 20 (Tween®20); polysorbate 60 (Tween®60);polysorbate 65 (Tween®65); polysorbate 80 (Tween®80); polysorbate 85(Tween®85); polyoxyethylene monostearate; surfactin; a poloxomer; asorbitan fatty acid ester such as sorbitan trioleate; lecithin;lysolecithin; phosphatidylserine; phosphatidylinositol; sphingomyelin;phosphatidylethanolamine (cephalin); cardiolipin; phosphatidic acid;cerebroside; dicetylphosphate; dipalmitoylphosphatidylglycerol;stearylamine; dodecylamine; hexadecyl-amine; acetyl palmitate; glycerolricinoleate; hexadecyl sterate; isopropyl myristate; tyloxapol;poly(ethylene glycol)5000-phosphatidylethanolamine; poly(ethyleneglycol)400-monostearate; phospholipid; synthetic and/or naturaldetergent having high surfactant properties; deoxycholate; cyclodextrin;chaotropic salt; ion pairing agent; glucose, fructose, galactose,ribose, lactose, sucrose, maltose, trehalose, cellbiose, mannose,xylose, arabinose, glucoronic acid, galactoronic acid, mannuronic acid,glucosamine, galatosamine, and neuramic acid; pullulan, cellulose,microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC),hydroxycellulose (HC), methylcellulose (MC), dextran, cyclodextran,glycogen, hydroxyethylstarch, carageenan, glycon, amylose, chitosan,N,O-carboxylmethylchitosan, algin and alginic acid, starch, chitin,inulin, konjac, glucommannan, pustulan, heparin, hyaluronic acid,curdlan, and xanthan, mannitol, sorbitol, xylitol, erythritol, maltitol,and lactitol, a pluronic polymer, polyethylene, polycarbonate (e.g.poly(1,3-dioxan-2one)), polyanhydride (e.g. poly(sebacic anhydride)),polypropylfumerate, polyamide (e.g. polycaprolactam), polyacetal,polyether, polyester (e.g., polylactide, polyglycolide,polylactide-co-glycolide, polycaprolactone, polyhydroxyacid (e.g.poly((β-hydroxyalkanoate))), poly(orthoester), polycyanoacrylate,polyvinyl alcohol, polyurethane, polyphosphazene, polyacrylate,polymethacrylate, polyurea, polystyrene, and polyamine, polylysine,polylysine-PEG copolymer, and poly(ethyleneimine), poly(ethyleneimine)-PEG copolymer, glycerol monocaprylocaprate, propylene glycol,Vitamin E TPGS (also known as d-α-Tocopheryl polyethylene glycol 1000succinate), gelatin, titanium dioxide, polyvinylpyrrolidone (PVP),hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC),methyl cellulose (MC), block copolymers of ethylene oxide and propyleneoxide (PEO/PPO), polyethyleneglycol (PEG), sodium carboxymethylcellulose(NaCMC), hydroxypropylmethyl cellulose acetate succinate (HPMCAS).

In some embodiments, the pharmaceutical preparation may include polymersfor controlled delivery of the described compounds, including, but notlimited to pluronic polymers, polyesters (e.g., polylactic acid,poly(lactic-co-glycolic acid), polycaprolactone, polyvalerolactone,poly(1,3-dioxan-2one)); polyanhydrides (e.g., poly(sebacic anhydride));polyethers (e.g., polyethylene glycol); polyurethanes;polymethacrylates; polyacrylates; and polycyanoacrylates. In someembodiments, polymers may be modified with polyethylene glycol (PEG),with a carbohydrate, and/or with acyclic polyacetals derived frompolysaccharides. See, e.g., Papisov, 2001, ACS Symposium Series,786:301, incorporated by reference herein.

The compounds of the present invention can be formulated as particles.In one embodiment the particles are or include microparticles. In analternative embodiment the particles are or include nanoparticles.

In an additional alternative embodiment, common techniques for preparingparticles include, but are not limited to, solvent evaporation, solventremoval, spray drying, phase inversion, coacervation, and lowtemperature casting. Suitable methods of particle formulation arebriefly described below. Pharmaceutically acceptable excipients,including pH modifying agents, disintegrants, preservatives, andantioxidants, can optionally be incorporated into the particles duringparticle formation.

In one embodiment, the particles are derived through a solventevaporation method. In this method, a compound described herein (orpolymer matrix and one or more compounds described herein) is dissolvedin a volatile organic solvent, such as methylene chloride. The organicsolution containing a compound described herein is then suspended in anaqueous solution that contains a surface active agent such as poly(vinylalcohol). The resulting emulsion is stirred until most of the organicsolvent evaporated, leaving solid nanoparticles or microparticles. Theresulting nanoparticles or microparticles are washed with water anddried overnight in a lyophilizer. Nanoparticles with different sizes andmorphologies can be obtained by this method.

Pharmaceutical compositions which contain labile polymers, such ascertain polyanhydrides, may degrade during the fabrication process dueto the presence of water. For these polymers, methods which areperformed in completely or substantially anhydrous organic solvents canbe used to make the particles.

Solvent removal can also be used to prepare particles from a compoundthat is hydrolytically unstable. In this method, the compound (orpolymer matrix and one or more compounds) is dispersed or dissolved in avolatile organic solvent such as methylene chloride. This mixture isthen suspended by stirring in an organic oil (such as silicon oil) toform an emulsion. Solid particles form from the emulsion, which cansubsequently be isolated from the supernatant. The external morphologyof spheres produced with this technique is highly dependent on theidentity of the drug.

In one embodiment an active compound as described herein is administeredto a patient in need thereof as particles formed by solvent removal. Inanother embodiment the present invention provides particles formed bysolvent removal comprising a compound of the present invention and oneor more pharmaceutically acceptable excipients as defined herein. Inanother embodiment the particles formed by solvent removal comprise acompound of the present invention and an additional therapeutic agent.In a further embodiment the particles formed by solvent removal comprisea compound of the present invention, an additional therapeutic agent,and one or more pharmaceutically acceptable excipients. In anotherembodiment any of the described particles formed by solvent removal canbe formulated into a tablet and then coated to form a coated tablet. Inan alternative embodiment the particles formed by solvent removal areformulated into a tablet but the tablet is uncoated.

In one embodiment, the particles are derived by spray drying. In thismethod, a compound (or polymer matrix and one or more compounds) isdissolved in an organic solvent such as methylene chloride. The solutionis pumped through a micronizing nozzle driven by a flow of compressedgas, and the resulting aerosol is suspended in a heated cyclone of air,allowing the solvent to evaporate from the micro droplets, formingparticles. Microparticles and nanoparticles can be obtained using thismethod.

In one embodiment an active compound as described herein is administeredto a patient in need thereof as a spray dried dispersion (SDD). Inanother embodiment the present invention provides a spray drieddispersion (SDD) comprising a compound of the present invention and oneor more pharmaceutically acceptable excipients as defined herein. Inanother embodiment the SDD comprises a compound of the present inventionand an additional therapeutic agent. In a further embodiment the SDDcomprises a compound of the present invention, an additional therapeuticagent, and one or more pharmaceutically acceptable excipients. Inanother embodiment any of the described spray dried dispersions can becoated to form a coated tablet. In an alternative embodiment the spraydried dispersion is formulated into a tablet but is uncoated.

Particles can be formed from the active compound as described hereinusing a phase inversion method. In this method, the compound (or polymermatrix and one or more active compounds) is dissolved in a suitablesolvent, and the solution is poured into a strong non-solvent for thecompound to spontaneously produce, under favorable conditions,microparticles or nanoparticles. The method can be used to producenanoparticles in a wide range of sizes, including, for example, fromnanoparticles to microparticles, typically possessing a narrow particlesize distribution.

In one embodiment, an active compound as described herein isadministered to a patient in need thereof as particles formed by phaseinversion. In another embodiment the present invention providesparticles formed by phase inversion comprising a compound of the presentinvention and one or more pharmaceutically acceptable excipients asdefined herein. In another embodiment the particles formed by phaseinversion comprise a compound of the present invention and an additionaltherapeutic agent. In a further embodiment the particles formed by phaseinversion comprise a compound of the present invention, an additionaltherapeutic agent, and one or more pharmaceutically acceptableexcipients. In another embodiment any of the described particles formedby phase inversion can be formulated into a tablet and then coated toform a coated tablet. In an alternative embodiment the particles formedby phase inversion are formulated into a tablet but the tablet isuncoated.

Techniques for particle formation using coacervation are known in theart, for example, as described in GB-B-929 406; GB-B-929 40 1; and U.S.Pat. Nos. 3,266,987, 4,794,000, and 4,460,563. Coacervation involves theseparation of a compound (or polymer matrix and one or more compounds)solution into two immiscible liquid phases. One phase is a densecoacervate phase, which contains a high concentration of the compound,while the second phase contains a low concentration of the compound.Within the dense coacervate phase, the compound forms nanoscale ormicroscale droplets, which harden into particles. Coacervation may beinduced by a temperature change, addition of a non-solvent or additionof a micro-salt (simple coacervation), or by the addition of anotherpolymer thereby forming an interpolymer complex (complex coacervation).

In one embodiment an active compound as described herein is administeredto a patient in need thereof as particles formed by coacervation. Inanother embodiment the present invention provides particles formed bycoacervation comprising a compound of the present invention and one ormore pharmaceutically acceptable excipients as defined herein. Inanother embodiment the particles formed by coacervation comprise acompound of the present invention and an additional therapeutic agent.In a further embodiment the particles formed by coacervation comprise acompound of the present invention, an additional therapeutic agent, andone or more pharmaceutically acceptable excipients. In anotherembodiment any of the described particles formed by coacervation can beformulated into a tablet and then coated to form a coated tablet. In analternative embodiment the particles formed by coacervation areformulated into a tablet but the tablet is uncoated.

Methods for very low temperature casting of controlled releasemicrospheres are described in U.S. Pat. No. 5,019,400 to Gombotz et al.In this method, the compound is dissolved in a solvent. The mixture isthen atomized into a vessel containing a liquid non-solvent at atemperature below the freezing point of the drug solution which freezesthe compound droplets. As the droplets and non-solvent for the compoundare warmed, the solvent in the droplets thaws and is extracted into thenon-solvent, hardening the microspheres.

In one embodiment, a compound of the present invention is administeredto a patient in need thereof as particles formed by low temperaturecasting. In another embodiment the present invention provides particlesformed by low temperature casting comprising a compound of the presentinvention and one or more pharmaceutically acceptable excipients asdefined herein. In another embodiment the particles formed by lowtemperature casting comprise a compound of the present invention and anadditional therapeutic agent. In a further embodiment the particlesformed by low temperature casting comprise a compound of the presentinvention, an additional therapeutic agent, and one or morepharmaceutically acceptable excipients. In another embodiment any of thedescribed particles formed by low temperature casting can be formulatedinto a tablet and then coated to form a coated tablet. In an alternativeembodiment the particles formed by low temperature casting areformulated into a tablet but the tablet is uncoated.

In one aspect of the present invention, an effective amount of an activecompound as described herein is incorporated into a nanoparticle, e.g.for convenience of delivery and/or extended release delivery. The use ofmaterials in nanoscale provides one the ability to modify fundamentalphysical properties such as solubility, diffusivity, blood circulationhalf-life, drug release characteristics, and/or immunogenicity. A numberof nanoparticle-based therapeutic and diagnostic agents have beendeveloped for the treatment of cancer, diabetes, pain, asthma, allergy,and infections. These nanoscale agents may provide more effective and/ormore convenient routes of administration, lower therapeutic toxicity,extend the product life cycle, and ultimately reduce health-care costs.As therapeutic delivery systems, nanoparticles can allow targeteddelivery and controlled release.

In addition, nanoparticle-based compound delivery can be used to releasecompounds at a sustained rate and thus lower the frequency ofadministration, deliver drugs in a targeted manner to minimize systemicside effects, or deliver two or more drugs simultaneously forcombination therapy to generate a synergistic effect and suppress drugresistance. A number of nanotechnology-based therapeutic products havebeen approved for clinical use. Among these products, liposomal drugsand polymer-based conjugates account for a large proportion of theproducts. See, Zhang, L., et al., Nanoparticles in Medicine: TherapeuticApplications and Developments, Clin. Pharm. and Ther., 83(5):761-769,2008.

Methods for producing nanoparticles are known in the art. For example,see Muller, R. H., et al., Solid lipid nanoparticles (SLN) forcontrolled drug delivery—a review of the state of the art, Eur. H.Pharm. Biopharm., 50:161-177, 2000; U.S. Pat. No. 8,691,750 to Consienet al.; WO 2012/145801 to Kanwar. U.S. Pat. No. 8,580,311 to Armes, S.et al.; Petros, R. A. and DeSimone, J. M., Strategies in the design ofnanoparticles for therapeutic applications, Nature Reviews/DrugDiscovery, vol. 9:615-627, 2010; U.S. Pat. Nos. 8,465,775; 8,444,899;8,420,124; 8,263,129; 8,158,728; 8,268,446; Pellegrino et al., 2005,Small, 1:48; Murray et al., 2000, Ann. Rev. Mat. Sci., 30:545; andTrindade et al., 2001, Chem. Mat., 13:3843; all incorporated herein byreference. Additional methods have been described in the literature(see, e.g., Doubrow, Ed., “Microcapsules and Nanoparticles in Medicineand Pharmacy,” CRC Press, Boca Raton, 1992; Mathiowitz et al., 1987, J.Control. Release, 5:13; Mathiowitz et al., 1987, Reactive Polymers,6:275; and Mathiowitz et al., 1988, J. Appl. Polymer Sci., 35:755; U.S.Pat. Nos. 5,578,325 and 6,007,845; P. Paolicelli et al.,“Surface-modified PLGA-based Nanoparticles that can EfficientlyAssociate and Deliver Virus-like Particles” Nanomedicine. 5(6):843-853(2010)), U.S. Pat. No. 5,543,158 to Gref et al., or WO publicationWO2009/051837 by Von Andrian et al. Zauner et al., 1998, Adv. Drug Del.Rev., 30:97; and Kabanov et al., 1995, Bioconjugate Chem., 6:7; (PEI;Boussif et al., 1995, Proc. Natl. Acad. Sci., USA, 1995, 92:7297), andpoly(amidoamine) dendrimers (Kukowska-Latallo et al., 1996, Proc. Natl.Acad. Sci., USA, 93:4897; Tang et al., 1996, Bioconjugate Chem., 7:703;and Haensler et al., 1993, Bioconjugate Chem., 4:372; Putnam et al.,1999, Macromolecules, 32:3658; Barrera et al., 1993, J. Am. Chem. Soc.,115:11010; Kwon et al., 1989, Macromolecules, 22:3250; Lim et al., 1999,J. Am. Chem. Soc., 121:5633; and Zhou et al., 1990, Macromolecules,23:3399). Examples of these polyesters includepoly(L-lactide-co-L-lysine) (Barrera et al., 1993, J. Am. Chem. Soc.,115:11010), poly(serine ester) (Zhou et al., 1990, Macromolecules,23:3399), poly(4-hydroxy-L-proline ester) (Putnam et al., 1999,Macromolecules, 32:3658; and Lim et al., 1999, J. Am. Chem. Soc.,121:5633), and poly(4-hydroxy-L-proline ester) (Putnam et al., 1999,Macromolecules, 32:3658; and Lim et al., 1999, J. Am. Chem. Soc.,121:5633; U.S. Pat. Nos. 6,123,727; 5,804,178; 5,770,417; 5,736,372;5,716,404; 6,095,148; 5,837,752; 5,902,599; 5,696,175; 5,514,378;5,512,600; 5,399,665; 5,019,379; 5,010,167; 4,806,621; 4,638,045; and4,946,929; Wang et al., 2001, J. Am. Chem. Soc., 123:9480; Lim et al.,2001, J. Am. Chem. Soc., 123:2460; Langer, 2000, Acc. Chem. Res., 33:94;Langer, 1999, J. Control. Release, 62:7; and Uhrich et al., 1999, Chem.Rev., 99:3181; Concise Encyclopedia of Polymer Science and PolymericAmines and Ammonium Salts, Ed. by Goethals, Pergamon Press, 1980;Principles of Polymerization by Odian, John Wiley & Sons, FourthEdition, 2004; Contemporary Polymer Chemistry by Allcock et al.,Prentice-Hall, 1981; Deming et al., 1997, Nature, 390:386; and in U.S.Pat. Nos. 6,506,577, 6,632,922, 6,686,446, and 6,818,732; C. Astete etal., “Synthesis and characterization of PLGA nanoparticles” J. Biomater.Sci. Polymer Edn, Vol. 17, No. 3, pp. 247-289 (2006); K. Avgoustakis“Pegylated Poly(Lactide) and Poly(Lactide-Co-Glycolide) Nanoparticles:Preparation, Properties and Possible Applications in Drug Delivery”Current Drug Delivery 1:321-333 (2004); C. Reis et al.,“Nanoencapsulation I. Methods for preparation of drug-loaded polymericnanoparticles” Nanomedicine 2:8-21 (2006); P. Paolicelli et al.,“Surface-modified PLGA-based Nanoparticles that can EfficientlyAssociate and Deliver Virus-like Particles” Nanomedicine. 5(6):843-853(2010); U.S. Pat. No. 6,632,671 to Unger Oct. 14, 2003, all incorporatedherein by reference.

In one embodiment, the polymeric particle is between about 0.1 nm toabout 10000 nm, between about 1 nm to about 1000 nm, between about 10 nmand 1000 nm, between about 1 and 100 nm, between about 1 and 10 nm,between about 1 and 50 nm, between about 100 nm and 800 nm, betweenabout 400 nm and 600 nm, or about 500 nm. In one embodiment, themicro-particles are no more than about 0.1 nm, 0.5 nm, 1.0 nm, 5.0 nm,10 nm, 25 nm, 50 nm, 75 nm, 100 nm, 150 nm, 200 nm, 250 nm, 300 nm, 400nm, 450 nm, 500 nm, 550 nm, 600 nm, 650 nm, 700 nm, 750 nm, 800 nm, 850nm, 900 nm, 950 nm, 1000 nm, 1250 nm, 1500 nm, 1750 nm, or 2000 nm. Insome embodiments, a compound described herein may be covalently coupledto a polymer used in the nanoparticle, for example a polystyreneparticle, PLGA particle, PLA particle, or other nanoparticle.

The pharmaceutical compositions can be formulated for oraladministration. These compositions can contain any amount of activecompound that achieves the desired result, for example between 0.1 and99 weight % (wt. %) of the compound and usually at least about 5 wt. %of the compound. Some embodiments contain at least about 10%, 15%, 20%,25 wt. % to about 50 wt. % or from about 5 wt. % to about 75 wt. % ofthe compound.

Pharmaceutical compositions suitable for rectal administration aretypically presented as unit dose suppositories. These may be prepared byadmixing the active compound with one or more conventional solidcarriers, for example, cocoa butter, and then shaping the resultingmixture.

Pharmaceutical compositions suitable for topical application to the skinpreferably take the form of an ointment, cream, lotion, paste, gel,spray, aerosol, or oil. Carriers which may be used include petroleumjelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers,and combinations of two or more thereof.

Pharmaceutical compositions suitable for transdermal administration maybe presented as discrete patches adapted to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time.Pharmaceutical compositions suitable for transdermal administration mayalso be delivered by iontophoresis (see, for example, PharmaceuticalResearch 3 (6):318 (1986)) and typically take the form of an optionallybuffered aqueous solution of the active compound. In one embodiment,microneedle patches or devices are provided for delivery of drugs acrossor into biological tissue, particularly the skin. The microneedlepatches or devices permit drug delivery at clinically relevant ratesacross or into skin or other tissue barriers, with minimal or no damage,pain, or irritation to the tissue.

Pharmaceutical compositions suitable for administration to the lungs canbe delivered by a wide range of passive breath driven and active powerdriven single/-multiple dose dry powder inhalers (DPI). The devices mostcommonly used for respiratory delivery include nebulizers, metered-doseinhalers, and dry powder inhalers. Several types of nebulizers areavailable, including jet nebulizers, ultrasonic nebulizers, andvibrating mesh nebulizers. Selection of a suitable lung delivery devicedepends on parameters, such as nature of the drug and its formulation,the site of action, and pathophysiology of the lung.

Additional non-limiting examples of inhalation drug delivery devices andmethods include, for example, U.S. Pat. No. 7,383,837 titled “Inhalationdevice” (SmithKline Beecham Corporation); WO/2006/033584 titled “Powderinhaler” (Glaxo SmithKline Pharmaceuticals SA); WO/2005/044186 titled“Inhalable pharmaceutical formulations employing desiccating agents andmethods of administering the same” (Glaxo Group Ltd and SmithKlineBeecham Corporation); U.S. Pat. No. 9,095,670 titled “Inhalation deviceand method of dispensing medicament”, U.S. Pat. No. 8,205,611 titled“Dry powder inhaler” (Astrazeneca AB); WO/2013/038170 titled “Inhaler”(Astrazeneca AB and Astrazeneca UK Ltd.); US/2014/0352690 titled“Inhalation Device with Feedback System”, U.S. Pat. No. 8,910,625 andUS/2015/0165137 titled “Inhalation Device for Use in Aerosol Therapy”(Vectura GmbH); U.S. Pat. No. 6,948,496 titled “Inhalers”,US/2005/0152849 titled “Powders comprising anti-adherent materials foruse in dry powder inhalers”, U.S. Pat. Nos. 6,582,678, 8,137,657,US/2003/0202944, and US/2010/0330188 titled “Carrier particles for usein dry powder inhalers”, U.S. Pat. No. 6,221,338 titled “Method ofproducing particles for use in dry powder inhalers”, U.S. Pat. No.6,989,155 titled “Powders”, US/2007/0043030 titled “Pharmaceuticalcompositions for treating premature ejaculation by pulmonaryinhalation”, U.S. Pat. No. 7,845,349 titled “Inhaler”, US/2012/0114709and U.S. Pat. No. 8,101,160 titled “Formulations for Use in InhalerDevices”, US/2013/0287854 titled “Compositions and Uses”,US/2014/0037737 and U.S. Pat. No. 8,580,306 titled “Particles for Use ina Pharmaceutical Composition”, US/2015/0174343 titled “Mixing Channelfor an Inhalation Device”, U.S. Pat. No. 7,744,855 and US/2010/0285142titled “Method of making particles for use in a pharmaceuticalcomposition”, U.S. Pat. No. 7,541,022, US/2009/0269412, andUS/2015/0050350 titled “Pharmaceutical formulations for dry powderinhalers” (Vectura Limited).

Many methods and devices for drug delivery to the eye are known in theart. Non-limiting examples are described in the following patents andpatent applications (fully incorporated herein by reference). Examplesare U.S. Pat. No. 8,192,408 titled “Ocular trocar assembly” (Psivida Us,Inc.); U.S. Pat. No. 7,585,517 titled “Transcleral delivery” (Macusight,Inc.); U.S. Pat. Nos. 5,710,182 and 5,795,913 titled “Ophthalmiccomposition” (Santen OY); U.S. Pat. No. 8,663,639 titled “Formulationsfor treating ocular diseases and conditions”, U.S. Pat. No. 8,486,960titled “Formulations and methods for vascular permeability-relateddiseases or conditions”, U.S. Pat. Nos. 8,367,097 and 8,927,005 titled“Liquid formulations for treatment of diseases or conditions”, U.S. Pat.No. 7,455,855 titled “Delivering substance and drug delivery systemusing the same” (Santen Pharmaceutical Co., Ltd.); WO/2011/050365 titled“Conformable Therapeutic Shield For Vision and Pain” and WO/2009/145842titled “Therapeutic Device for Pain Management and Vision” (ForsightLabs, LLC); U.S. Pat. Nos. 9,066,779 and 8,623,395 titled “Implantabletherapeutic device”, WO/2014/160884 titled “Ophthalmic Implant forDelivering Therapeutic Substances”, U.S. Pat. Nos. 8,399,006, 8,277,830,8,795,712, 8,808,727, 8,298,578, and WO/2010/088548 titled “Posteriorsegment drug delivery”, WO/2014/152959 and US20140276482 titled “Systemsfor Sustained Intraocular Delivery of Low Solubility Compounds from aPort Delivery System Implant”, U.S. Pat. Nos. 8,905,963 and 9,033,911titled “Injector apparatus and method for drug delivery”, WO/2015/057554titled “Formulations and Methods for Increasing or Reducing Mucus”, U.S.Pat. Nos. 8,715,712 and 8,939,948 titled “Ocular insert apparatus andmethods”, WO/2013/116061 titled “Insertion and Removal Methods andApparatus for Therapeutic Devices”, WO/2014/066775 titled “OphthalmicSystem for Sustained Release of Drug to the Eye”, WO/2015/085234 andWO/2012/019176 titled “Implantable Therapeutic Device”, WO/2012/065006titled “Methods and Apparatus to determine Porous Structures for DrugDelivery”, WO/2010/141729 titled “Anterior Segment Drug Delivery”,WO/2011/050327 titled “Corneal Denervation for Treatment of OcularPain”, WO/2013/022801 titled “Small Molecule Delivery with ImplantableTherapeutic Device”, WO/2012/019047 titled “Subconjunctival Implant forPosterior Segment Drug Delivery”, WO/2012/068549 titled “TherapeuticAgent Formulations for Implanted Devices”, WO/2012/019139 titled“Combined Delivery Methods and Apparatus”, WO/2013/040426 titled “OcularInsert Apparatus and Methods”, WO/2012/019136 titled “Injector Apparatusand Method for Drug Delivery”, WO/2013/040247 titled “Fluid ExchangeApparatus and Methods” (ForSight Vision4, Inc.).

Additional non-limiting examples of how to deliver the active compoundsare provided in WO/2015/085251 titled “Intracameral Implant forTreatment of an Ocular Condition” (Envisia Therapeutics, Inc.);WO/2011/008737 titled “Engineered Aerosol Particles, and AssociatedMethods”, WO/2013/082111 titled “Geometrically Engineered Particles andMethods for Modulating Macrophage or Immune Responses”, WO/2009/132265titled “Degradable compounds and methods of use thereof, particularlywith particle replication in non-wetting templates”, WO/2010/099321titled “Interventional drug delivery system and associated methods”,WO/2008/100304 titled “Polymer particle composite having high fidelityorder, size, and shape particles”, WO/2007/024323 titled “Nanoparticlefabrication methods, systems, and materials” (Liquidia Technologies,Inc. and the University of North Carolina at Chapel Hill);WO/2010/009087 titled “Iontophoretic Delivery of a Controlled-ReleaseFormulation in the Eye”, (Liquidia Technologies, Inc. and EyegatePharmaceuticals, Inc.) and WO/2009/132206 titled “Compositions andMethods for Intracellular Delivery and Release of Cargo”, WO/2007/133808titled “Nano-particles for cosmetic applications”, WO/2007/056561 titled“Medical device, materials, and methods”, WO/2010/065748 titled “Methodfor producing patterned materials”, WO/2007/081876 titled“Nanostructured surfaces for biomedical/biomaterial applications andprocesses thereof” (Liquidia Technologies, Inc.).

Additional non-limiting examples of methods and devices for drugdelivery to the eye include, for example, WO2011/106702 and U.S. Pat.No. 8,889,193 titled “Sustained delivery of therapeutic agents to an eyecompartment”, WO2013/138343 and U.S. Pat. No. 8,962,577 titled“Controlled release formulations for the delivery of HIF-1 inhibitors”,WO/2013/138346 and US2013/0272994 titled “Non-Linear MultiblockCopolymer-Drug Conjugates for the Delivery of Active Agents”,WO2005/072710 and U.S. Pat. No. 8,957,034 titled “Drug and Gene CarrierParticles that Rapidly Move Through Mucus Barriers”, WO2008/030557,US2010/0215580, US2013/0164343 titled “Compositions and Methods forEnhancing Transport Through Mucous”, WO2012/061703, US2012/0121718, andUS2013/0236556 titled “Compositions and Methods Relating to ReducedMucoadhesion”, WO2012/039979 and US2013/0183244 titled “Rapid Diffusionof Large Polymeric Nanoparticles in the Mammalian Brain”, WO2012/109363and US2013/0323313 titled “Mucus Penetrating Gene Carriers”, WO2013/090804 and US2014/0329913 titled “Nanoparticles with enhancedmucosal penetration or decreased inflammation”, WO2013/110028 titled“Nanoparticle formulations with enhanced mucosal penetration”,WO2013/166498 and US2015/0086484 titled “Lipid-based drug carriers forrapid penetration through mucus linings” (The Johns Hopkins University);WO2013/166385 titled “Pharmaceutical Nanoparticles Showing ImprovedMucosal Transport”, US2013/0323179 titled “Nanocrystals, Compositions,And Methods that Aid Particle Transport in Mucus” (The Johns HopkinsUniversity and Kala Pharmaceuticals, Inc.); WO/2015/066444 titled“Compositions and methods for ophthalmic and/or other applications”,WO/2014/020210 and WO/2013/166408 titled “Pharmaceutical nanoparticlesshowing improved mucosal transport” (Kala Pharmaceuticals, Inc.); U.S.Pat. No. 9,022,970 titled “Ophthalmic injection device including dosagecontrol device”, WO/2011/153349 titled “Ophthalmic compositionscomprising pbo-peo-pbo block copolymers”, WO/2011/140203 titled“Stabilized ophthalmic galactomannan formulations”, WO/2011/068955titled “Ophthalmic emulsion”, WO/2011/037908 titled “Injectable aqueousophthalmic composition and method of use therefor”, US2007/0149593titled “Pharmaceutical Formulation for Delivery of Receptor TyrosineKinase Inhibiting (RTKi) Compounds to the Eye”, U.S. Pat. No. 8,632,809titled “Water insoluble polymer matrix for drug delivery” (Alcon, Inc.).

Additional non-limiting examples of drug delivery devices and methodsinclude, for example, US20090203709 titled “Pharmaceutical Dosage FormFor Oral Administration Of Tyrosine Kinase Inhibitor” (AbbottLaboratories); US20050009910 titled “Delivery of an active drug to theposterior part of the eye via subconjunctival or periocular delivery ofa prodrug”, US 20130071349 titled “Biodegradable polymers for loweringintraocular pressure”, U.S. Pat. No. 8,481,069 titled “Tyrosine kinasemicrospheres”, U.S. Pat. No. 8,465,778 titled “Method of making tyrosinekinase microspheres”, U.S. Pat. No. 8,409,607 titled “Sustained releaseintraocular implants containing tyrosine kinase inhibitors and relatedmethods”, U.S. Pat. No. 8,512,738 and US 2014/0031408 titled“Biodegradable intravitreal tyrosine kinase implants”, US 2014/0294986titled “Microsphere Drug Delivery System for Sustained IntraocularRelease”, U.S. Pat. No. 8,911,768 titled “Methods For TreatingRetinopathy With Extended Therapeutic Effect” (Allergan, Inc.); U.S.Pat. No. 6,495,164 titled “Preparation of injectable suspensions havingimproved injectability” (Alkermes Controlled Therapeutics, Inc.); WO2014/047439 titled “Biodegradable Microcapsules Containing FillingMaterial” (Akina, Inc.); WO 2010/132664 titled “Compositions And MethodsFor Drug Delivery” (Baxter International Inc. Baxter Healthcare SA);US20120052041 titled “Polymeric nanoparticles with enhanced drugloadingand methods of use thereof” (The Brigham and Women's Hospital, Inc.);US20140178475, US20140248358, and US20140249158 titled “TherapeuticNanoparticles Comprising a Therapeutic Agent and Methods of Making andUsing Same” (BIND Therapeutics, Inc.); U.S. Pat. No. 5,869,103 titled“Polymer microparticles for drug delivery” (Danbiosyst UK Ltd.); U.S.Pat. No. 8,628,801 titled “Pegylated Nanoparticles” (Universidad deNavarra); US2014/0107025 titled “Ocular drug delivery system” (JadeTherapeutics, LLC); U.S. Pat. No. 6,287,588 titled “Agent deliveringsystem comprised of microparticle and biodegradable gel with an improvedreleasing profile and methods of use thereof”, U.S. Pat. No. 6,589,549titled “Bioactive agent delivering system comprised of microparticleswithin a biodegradable to improve release profiles” (Macromed, Inc.);U.S. Pat. Nos. 6,007,845 and 5,578,325 titled “Nanoparticles andmicroparticles of non-linear hydrophilichydrophobic multiblockcopolymers” (Massachusetts Institute of Technology); US20040234611,US20080305172, US20120269894, and US20130122064 titled “Ophthalmic depotformulations for periocular or subconjunctival administration (NovartisAg); U.S. Pat. No. 6,413,539 titled “Block polymer” (Poly-Med, Inc.); US20070071756 titled “Delivery of an agent to ameliorate inflammation”(Peyman); US 20080166411 titled “Injectable Depot Formulations AndMethods For Providing Sustained Release Of Poorly Soluble DrugsComprising Nanoparticles” (Pfizer, Inc.); U.S. Pat. No. 6,706,289 titled“Methods and compositions for enhanced delivery of bioactive molecules”(PR Pharmaceuticals, Inc.); and U.S. Pat. No. 8,663,674 titled“Microparticle containing matrices for drug delivery” (Surmodics).

IV. Uses of Active Compounds for Treatment of Selected Disorders

In one aspect, an effective amount of an active compound or its salt orcomposition as described herein is used to treat a medical disorderwhich is an inflammatory or immune condition, a disorder mediated by thecomplement cascade (including a dysfunctional cascade) including acomplement D-related disorder, a disorder or abnormality of a cell thatadversely affects the ability of the cell to engage in or respond tonormal complement activity, or an undesired complement-mediated responseto a medical treatment, such as surgery or other medical procedure or apharmaceutical or biopharmaceutical drug administration, a bloodtransfusion, or other allogenic tissue or fluid administration.

In one embodiment, the disorder is selected from fatty liver andconditions stemming from fatty liver, such as nonalcoholicsteatohepatitis (NASH), liver inflammation, cirrhosis and liver failure.In one embodiment of the present invention, a method is provided fortreating fatty liver disease in a host by administering an effectiveamount of an active compound or its salt or composition as describedherein.

In another embodiment, an active compound or its salt or composition asdescribed herein is used to modulate an immune response prior to orduring surgery or other medical procedure. One non-limiting example isuse in connection with acute or chronic graft versus host disease, whichis a common complication as a result of allogeneic tissue transplant,and can also occur as a result of a blood transfusion.

In one embodiment, the present invention provides a method of treatingor preventing dermatomyositis by administering to a subject in needthereof an effective amount of an active compound or its salt orcomposition as described herein.

In one embodiment, the present invention provides a method of treatingor preventing amyotrophic lateral sclerosis by administering to asubject in need thereof an effective amount of an active compound or itssalt or composition as described herein.

In another embodiment, a method is provided for the treatment orprevention of cytokine or inflammatory reactions in response to theadministration of pharmaceutical or biotherapeutic (e.g. CAR T-celltherapy or monoclonal antibody therapy) in a host by administering aneffective amount of an active compound or its salt or composition asdescribed herein. Various types of cytokine or inflammatory reactionsmay occur in response to a number of factors, such as theadministrations of biotherapeutics. In one embodiment, the cytokine orinflammatory reaction is cytokine release syndrome. In one embodiment,the cytokine or inflammatory reaction is tumor lysis syndrome (whichalso leads to cytokine release). Symptoms of cytokine release syndromerange from fever, headache, and skin rashes to bronchospasm, hypotensionand even cardiac arrest. Severe cytokine release syndrome is describedas cytokine storm, and can be fatal.

Fatal cytokine storms have been observed in response to infusion withseveral monoclonal antibody therapeutics. See, Abramowicz D, et al.“Release of tumor necrosis factor, interleukin-2, and gamma-interferonin serum after injection of OKT3 monoclonal antibody in kidneytransplant recipients” Transplantation (1989) 47(4):606-8; Chatenoud L,et al. “In vivo cell activation following OKT3 administration. Systemiccytokine release and modulation by corticosteroids” Transplantation(1990) 49(4):697-702; and Lim L C, Koh L P, and Tan P. “Fatal cytokinerelease syndrome with chimeric anti-CD20 monoclonal antibody rituximabin a 71-year-old patient with chronic lymphocytic leukemia” J. ClinOncol. (1999) 17(6):1962-3.

Also contemplated herein, is the use of an active compound or its saltor composition as described herein to mediate an adverse immune responsein patients receiving bi-specific T-cell engagers (BiTE). A bi-specificT-cell engager directs T-cells to target and bind with a specificantigen on the surface of a cancer cell. For example, Blinatumomab(Amgen), a BiTE has recently been approved as a second line therapy inPhiladelphia chromosome-negative relapsed or refractory acutelymphoblastic leukemia. Blinatumomab is given by continuous intravenousinfusion in 4-week cycles. The use of BiTE agents has been associatedwith adverse immune responses, including cytokine release syndrome. Themost significantly elevated cytokines in the CRS associated with ACTinclude IL-10, IL-6, and IFN-γ (Klinger et al., Immunopharmacologicresponse of patients with B-lineage acute lymphoblastic leukemia tocontinuous infusion of T cell-engaging CD19/CD3-bispecific BiTE antibodyblinatumomab. Blood (2012) 119:6226-6233).

In another embodiment, the disorder is episcleritis, idiopathicepiscleritis, anterior episcleritis, or posterior episcleritis. In oneembodiment, the disorder is idiopathic anterior uveitis, HLA-B27 relateduveitis, herpetic keratouveitis, Posner Schlossman syndrome, Fuch'sheterochromic iridocyclitis, or cytomegalovirus anterior uveitis.

In yet another embodiment, the disorder is selected from:

-   (i) vitritis, sarcoidosis, syphilis, tuberculosis, or Lyme disease;-   (ii) retinal vasculitis, Eales disease, tuberculosis, syphilis, or    toxoplasmosis;-   (iii) neuroretinitis, viral retinitis, or acute retinal necrosis;-   (iv) varicella zoster virus, herpes simplex virus, cytomegalovirus,    Epstein-Barr virus, lichen planus, or Dengue-associated disease    (e.g., hemorraghic Dengue Fever);-   (v) Masquerade syndrome, contact dermatitis, trauma induced    inflammation, UVB induced inflammation, eczema, granuloma annulare,    or acne.

In an additional embodiment, the disorder is selected from:

-   (i) acute myocardial infarction, aneurysm, cardiopulmonary bypass,    dilated cardiomyopathy, complement activation during cardiopulmonary    bypass operations, coronary artery disease, restenosis following    stent placement, or percutaneous transluminal coronary angioplasty    (PTCA);-   (ii) antibody-mediated transplant rejection, anaphylactic shock,    anaphylaxis, allogenic transplant, humoral and vascular transplant    rejection, graft dysfunction, graft-versus-host disease, Graves'    disease, adverse drug reactions, or chronic graft vasculopathy;-   (iii) allergic bronchopulmonary aspergillosis, allergic neuritis,    drug allergy, radiation-induced lung injury, eosinophilic pneumonia,    radiographic contrast media allergy, bronchiolitis obliterans, or    interstitial pneumonia;-   (iv) amyotrophic lateral sclerosis, parkinsonism-dementia complex,    sporadic frontotemporal dementia, frontotemporal dementia with    Parkinsonism linked to chromosome 17, frontotemporal lobar    degeneration, tangle only dementia, cerebral amyloid angiopathy,    cerebrovascular disorder, certain forms of frontotemporal dementia,    chronic traumatic encephalopathy (CTE), PD with dementia (PDD),    argyrophilic grain dementia, dementia pugilistica, dementia with    Lewy Bodies (DLB), or multi-infarct dementia;-   (v) Creutzfeldt-Jakob disease, Huntington's disease, multifocal    motor neuropathy (MMN), prion protein cerebral amyloid angiopathy,    polymyositis, postencephalitic parkinsonism, subacute sclerosing    panencephalitis, non-Guamanian motor neuron disease with    neurofibrillary tangles, neural regeneration, or diffuse    neurofibrillary tangles with calcification.

In one embodiment, the disorder is selected from:

-   (i) atopic dermatitis, dermatitis, dermatomyositis, dermatomyositis    bullous pemphigoid, scleroderma, sclerodermatomyositis, psoriatic    arthritis, pemphigus vulgaris, Discoid lupus erythematosus,    cutaneous lupus, chilblain lupus erythematosus, or lupus    erythematosus-lichen planus overlap syndrome.;-   (ii) cryoglobulinemic vasculitis, mesenteric/enteric vascular    disorder, peripheral vascular disorder, antineutrophil cytoplasm    antibody (ANCA)-associated vasculitis (AAV), TL-2 induced vascular    leakage syndrome, or immune complex vasculitis;-   (iii) angioedema, low platelets (HELLP) syndrome, sickle cell    disease, platelet refractoriness, red cell casts, or typical or    infectious hemolytic uremic syndrome (tHUS);-   (iv) hematuria, hemodialysis, hemolysis, hemorrhagic shock,    immunothrombocytopenic purpura (ITP), thrombotic thrombocytopenic    purpura (TTP), idiopathic thrombocytopenic purpura (ITP),    drug-induced thrombocytopenia, autoimmune hemolytic anemia (AIHA),    azotemia, blood vessel and/or lymph vessel inflammation, rotational    atherectomy, or delayed hemolytic transfusion reaction;-   (v) British type amyloid angiopathy, Buerger's disease, bullous    pemphigoid, C1q nephropathy, cancer, or catastrophic    antiphospholipid syndrome.

In another embodiment, the disorder is selected from:

-   (i) wet AMD, dry AMD, chorioretinal degeneration, choroidal    neovascularization (CNV), choroiditis, loss of RPE function, loss of    vision (including loss of visual acuity or visual field), loss of    vision from AMD, retinal damage in response to light exposure,    retinal degeneration, retinal detachment, retinal dysfunction,    retinal neovascularization (RNV), retinopathy of prematurity, or RPE    degeneration;-   (ii) pseudophakic bullous keratopathy, symptomatic macular    degeneration related disorder, optic nerve degeneration,    photoreceptor degeneration, cone degeneration, loss of photoreceptor    cells, pars planitis, scleritis, proliferative vitreoretinopathy, or    formation of ocular drusen;-   (iii) chronic urticaria, Churg-Strauss syndrome, cold agglutinin    disease (CAD), corticobasal degeneration (CBD), cryoglobulinemia,    cyclitis, damage of the Bruch's membrane, Degos disease, diabetic    angiopathy, elevated liver enzymes, endotoxemia, epidermolysis    bullosa, or epidermolysis bullosa acquisita;-   (iv) essential mixed cryoglobulinemia, excessive blood urea    nitrogen-BUN, focal segmental glomerulosclerosis,    Gerstmann-Straussler-Scheinker disease, giant cell arteritis, gout,    Hallervorden-Spatz disease, Hashimoto's thyroiditis,    Henoch-Schonlein purpura nephritis, or abnormal urinary sediments;-   (v) hepatitis, hepatitis A, hepatitis B, hepatitis C or human    immunodeficiency virus (HIV),-   (vi) a viral infection more generally, for example selected from    Flaviviridae, Retroviruses, Coronaviridae, Poxviridae, Adenoviridae,    Herpesviridae, Caliciviridae, Reoviridae, Picornaviridae,    Togaviridae, Orthomyxoviridae, Rhabdoviridae, or Hepadnaviridae;-   (vii) Neisseria meningitidis, shiga toxin E. coli-related hemolytic    uremic syndrome (STEC-HUS), Streptococcus, or poststreptococcal    glomerulonephritis.

In a further embodiment, the disorder is selected from:

-   (viii) hyperlipidemia, hypertension, hypoalbuminemia, hypobolemic    shock, hypocomplementemic urticarial vasculitis syndrome,    hypophosphastasis, hypovolemic shock, idiopathic pneumonia syndrome,    or idiopathic pulmonary fibrosis;-   (ix) inclusion body myositis, intestinal ischemia, iridocyclitis,    iritis, juvenile chronic arthritis, Kawasaki's disease (arteritis),    or lipiduria;-   (x) membranoproliferative glomerulonephritis (MPGN) I, microscopic    polyangiitis, mixed cryoglobulinemia, molybdenum cofactor deficiency    (MoCD) type A, pancreatitis, panniculitis, Pick's disease,    polyarteritis nodosa (PAN), progressive subcortical gliosis,    proteinuria, reduced glomerular filtration rate (GFR), or    renovascular disorder;-   (xi) multiple organ failure, multiple system atrophy (MSA), myotonic    dystrophy, Niemann-Pick disease type C, chronic demyelinating    diseases, or progressive supranuclear palsy;-   (xii) spinal cord injury, spinal muscular atrophy,    spondyloarthropathies, Reiter's syndrome, spontaneous fetal loss,    recurrent fetal loss, pre-eclampsia, synucleinopathy, Takayasu's    arteritis, post-partum thryoiditis, thyroiditis, Type I    cryoglobulinemia, Type II mixed cryoglobulinemia, Type III mixed    cryoglobulinemia, ulcerative colitis, uremia, urticaria, venous gas    embolus (VGE), or Wegener's granulomatosis;

In one embodiment, an active compound or its salt or composition asdescribed herein is useful for treating or preventing a disorderselected from autoimmune oophoritis, endometriosis, autoimmune orchitis,Ord's thyroiditis, autoimmune enteropathy, coeliac disease, Hashimoto'sencephalopathy, antiphospholipid syndrome (APLS) (Hughes syndrome),aplastic anemia, autoimmune lymphoproliferative syndrome (Canale-Smithsyndrome), autoimmune neutropenia, Evans syndrome, pernicious anemia,pure red cell aplasia, thrombocytopenia, adipose dolorosa (Dercum'sdisease), adult onset Still's disease, ankylosing spondylitis, CRESTsyndrome, drug-induced lupus, eosinophilic fasciitis (Shulman'ssyndrome), Felty syndrome, IgG4-related disease, mixed connective tissuedisease (MCTD), palindromic rheumatism (Hench-Rosenberg syndrome),Parry-Romberg syndrome, Parsonage-Turner syndrome, relapsingpolychondritis (Meyenburg-Altherr-Uehlinger syndrome), retroperitonialfibrosis, rheumatic fever, Schnitzler syndrome, fibromyalgia,neuromyotonia (Isaac's disease), paraneoplastic degeneration, autoimmuneinner ear disease, Meniere's disease, interstitial cystitis, autoimmunepancreatitis, zika virus-related disorders, chikungunya virus-relateddisorders, subacute bacterial endocarditis (SBE), IgA nephropathy, IgAvasculitis, polymyalgia rheumatic, rheumatoid vasculitis, alopeciaareata, autoimmune progesterone dermatitis, dermatitis herpetiformis,erythema nodosum, gestational pemphigoid, hidradenitis suppurativa,lichen sclerosus, linear IgA disease (LAD), morphea, myositis,pityriasis lichenoides et varioliformis acuta, vitiligo post-myocardialinfarction syndrome (Dressler's syndrome), post-pericardiotomy syndrome,autoimmune retinopathy, Cogan syndrome, Graves opthalmopathy, ligneousconjunctivitis, Mooren's ulcer, opsoclonus myoclonus syndrome, opticneuritis, retinocochleocerebral vasculopathy (Susac's syndrome),sympathetic opthalmia, Tolosa-Hunt syndrome, interstitial lung disease,antisynthetase syndrome, Addison's disease, autoimmune polyendocrinesyndrome (APS) type I, autoimmune polyendocrine syndrome (APS) type II,autoimmune polyendocrine syndrome (APS) type III, disseminated sclerosis(multiple sclerosis, pattern II), rapidly progressing glomerulonephritis(RPGN), juvenile rheumatoid arthritis, enthesitis-related arthritis,reactive arthritis (Reiter's syndrome), autoimmune hepatitis or lupoidhepatitis, primary biliary cirrhosis (PBS), primary sclerosingcholangitis, microscopic colitis, latent lupus (undifferentiatedconnective tissue disease (UCTD)), acute disseminated encephalomyelitis(ADEM), acute motor axonal neuropathy, anti-n-methyl-D-aspartatereceptor encephalitis, Balo concentric sclerosis (Schilders disease),Bickerstaff's encephalitis, chronic inflammatory demyelinatingpolyneuropathy, idiopathic inflammatory demyelinating disease,Lambert-Eaton mysathenic syndrome, Oshtoran syndrome, pediatricautoimmune neuropsychiatric disorder associated with Streptococcus(PANDAS), progressive inflammatory neuropathy, restless leg syndrome,stiff person syndrome, Sydenhem syndrome, transverse myelitis, lupusvasculitis, leukocytoclastic vasculitis, Microscopic Polyangiitis,polymyositis or ischemic-reperfusion injury of the eye.

In one embodiment, an active compound or its salt or composition asdescribed herein is useful for treating or preventing a disorder that ismediated by the complement pathway, and in particular, a pathway that ismodulated by complement Factor D. In another embodiment, the compound iseffective to treat the disorder, albeit through a different mechanism.

In certain embodiments, the disorder is an inflammatory disorder, animmune disorder, an autoimmune disorder, or complement Factor D relateddisorders in a host. In one embodiment, the disorder is an oculardisorder or an eye disorder.

Examples of eye disorders that may be treated according to thecompositions and methods disclosed herein include amoebic keratitis,fungal keratitis, bacterial keratitis, viral keratitis, onchorcercalkeratitis, bacterial keratoconjunctivitis, viral keratoconjunctivitis,corneal dystrophic diseases, Fuchs' endothelial dystrophy, Sjogren'ssyndrome, Stevens-Johnson syndrome, autoimmune dry eye diseases,environmental dry eye diseases, corneal neovascularization diseases,post-corneal transplant rejection prophylaxis and treatment, autoimmuneuveitis, infectious uveitis, anterior uveitis, posterior uveitis(including toxoplasmosis), pan-uveitis, an inflammatory disease of thevitreous or retina, endophthalmitis prophylaxis and treatment, macularedema, macular degeneration, age related macular degeneration,proliferative and non-proliferative diabetic retinopathy, hypertensiveretinopathy, an autoimmune disease of the retina, primary and metastaticintraocular melanoma, other intraocular metastatic tumors, open angleglaucoma, closed angle glaucoma, pigmentary glaucoma and combinationsthereof.

In a further embodiment, the disorder is selected from age-relatedmacular degeneration, glaucoma, diabetic retinopathy, neuromyelitisoptica (NMO), vasculitis, hemodialysis, blistering cutaneous diseases(including bullous pemphigoid, pemphigus, and epidermolysis bullosa),ocular cicatrical pemphigoid, uveitis, adult macular degeneration,diabetic retinopa retinitis pigmentosa, macular edema, Behcet's uveitis,multifocal choroiditis, Vogt-Koyangi-Harada syndrome, imtermediateuveitis, birdshot retino-chorioditis, sympathetic ophthalmia, oculardicatricial pemphigoid, ocular pemphigus, nonartertic ischemic opticneuropathy, postoperative inflammation, and retinal vein occlusion, oruveitis (including Behcet's disease and other sub-types of uveitis).

In some embodiments, complement mediated diseases include ophthalmicdiseases (including early or neovascular age-related maculardegeneration and geographic atrophy), autoimmune diseases (includingarthritis, rheumatoid arthritis), respiratory diseases, cardiovasculardiseases. In other embodiments, the compounds of the invention aresuitable for use in the treatment of diseases and disorders associatedwith fatty acid metabolism, including obesity and other metabolicdisorders.

Disorders that may be treated or prevented by an active compound or itssalt or composition as described herein also include, but are notlimited to:

-   (i) paroxysmal nocturnal hemoglobinuria (PNH), hereditary    angioedema, capillary leak syndrome, atypical hemolytic uremic    syndrome (aHUS), hemolytic uremic syndrome (HUS), abdominal aortic    aneurysm, hemodialysis complications, hemolytic anemia, or    hemodialysis;-   (ii) myasthenia gravis, multiple sclerosis, C3 glomerulonephritis    (C3GNs), MPGN II (dense deposit disease), neurological disorders,    Guillain Barre Syndrome, diseases of the central nervous system and    other neurodegenerative conditions, glomerulonephritis (including    membrane proliferative glomerulonephritis), SLE nephritis,    proliferative nephritis, liver fibrosis, tissue regeneration and    neural regeneration, or Barraquer-Simons Syndrome;-   (iii) inflammatory effects of sepsis, systemic inflammatory response    syndrome (SIRS), disorders of inappropriate or undesirable    complement activation, interleukin-2 induced toxicity during IL-2    therapy, inflammatory disorders, inflammation of autoimmune    diseases, system lupus erythematosus (SLE), Crohn's disease,    rheumatoid arthritis, inflammatory bowel disease, lupus nephritides,    arthritis, immune complex disorders and autoimmune diseases,    systemic lupus, or lupus erythematosus;-   (iv) ischemia/reperfusion injury (I/R injury), myocardial    infarction, myocarditis, post-ischemic reperfusion conditions,    balloon angioplasty, atherosclerosis, post-pump syndrome in    cardiopulmonary bypass or renal bypass, renal ischemia, mesenteric    artery reperfusion after aortic reconstruction, antiphospholipid    syndrome, autoimmune heart disease, ischemia-reperfusion injuries,    obesity, or diabetes;-   (v) Alzheimer's dementia, stroke, schizophrenia, traumatic brain    injury, trauma, Parkinson's disease, epilepsy, transplant rejection,    prevention of fetal loss, biomaterial reactions (e.g. in    hemodialysis, implants), hyperacute allograft rejection, xenograft    rejection, transplantation, psoriasis, burn injury, thermal injury    including burns or frostbite;-   (vi) asthma, allergy, acute respiratory distress syndrome (ARDS),    cystic fibrosis, adult respiratory distress syndrome, dyspnea,    hemoptysis, chronic obstructive pulmonary disease (COPD), emphysema,    pulmonary embolisms and infarcts, pneumonia, fibrogenic dust    diseases, inert dusts and minerals (e.g., silicon, coal dust,    beryllium, and asbestos), pulmonary fibrosis, organic dust diseases,    chemical injury (due to irritant gases and chemicals, e.g.,    chlorine, phosgene, sulfur dioxide, hydrogen sulfide, nitrogen    dioxide, ammonia, and hydrochloric acid), smoke injury, thermal    injury (e.g., burn, freeze), bronchoconstriction, hypersensitivity    pneumonitis, parasitic diseases, Goodpasture's Syndrome    (anti-glomerular basement membrane nephritis), pulmonary vasculitis,    Pauci-immune vasculitis, or immune complex-associated inflammation.

In one embodiment, a method for the treatment of paroxysmal nocturnalhemoglobinuria (PNH) in a host is provided that includes theadministration of an effective amount of an active compound or its saltor composition as described herein. In another embodiment, a method forthe treatment of age-related macular degeneration (AMD) in a host isprovided that includes the administration of an effective amount anactive compound or its salt or composition as described herein. Inanother embodiment, a method for the treatment of rheumatoid arthritisin a host is provided that includes the administration of an effectiveamount of an active compound or its salt or composition as describedherein. In another embodiment, a method for the treatment of multiplesclerosis in a host is provided that includes the administration of aneffective amount of an active compound or its salt or composition asdescribed herein. In another embodiment, a method for the treatment ofmyasthenia gravis in a host is provided that includes the administrationof an effective amount of an active compound or its salt or compositionas described herein. In another embodiment, a method for the treatmentof atypical hemolytic uremic syndrome (aHUS) in a host is provided thatincludes the administration of an effective amount of an active compoundor its salt or composition as described herein. In another embodiment, amethod for the treatment of C3 glomerulonephritis in host is providedthat includes the administration of an effective amount of an activecompound or its salt or composition as described herein. In anotherembodiment, a method for the treatment of abdominal aortic aneurysm inhost is provided that includes the administration of an effective amountof an active compound or its salt or composition as described herein. Inanother embodiment, a method for the treatment of neuromyelitis optica(NMO) in a host is provided that includes the administration of aneffective amount of an active compound or its salt or composition asdescribed herein.

In one embodiment, a method for the treatment of sickle cell in a hostis provided that includes the administration of an effective amount ofan active compound or its salt or composition as described herein. Inone embodiment, a method for the treatment of immunothrombocytopenicpurpura (ITP), thrombotic thrombocytopenic purpura (TTP), or idiopathicthrombocytopenic purpura (ITP) in a host is provided that includes theadministration of an effective amount of an active compound or its saltor composition as described herein. In one embodiment, a method for thetreatment of ANCA-vasculitis in a host is provided that includes theadministration of an effective amount of an active compound or its saltor composition as described herein. In one embodiment, a method for thetreatment of IgA nephropathy in a host is provided that includes theadministration of an effective amount of an active compound or its saltor composition as described herein. In one embodiment, a method for thetreatment of rapidly progressing glomerulonephritis (RPGN), in a host isprovided that includes the administration of an effective amount of anactive compound or its salt or composition as described herein. In oneembodiment, a method for the treatment of lupus nephritis, in a host isprovided that includes the administration of an effective amount of anactive compound or its salt or composition as described herein. In oneembodiment, a method for the treatment of hemorraghic dengue fever, in ahost is provided that includes the administration of an effective amountof an active compound or its salt or composition as described herein.

In some embodiments, the present invention provides methods of treatingor preventing an inflammatory disorder or a complement related disease,by administering to a host in need thereof an effective amount of anactive compound or its salt or composition as described herein. In someembodiments, the present invention provides methods of treating orpreventing an inflammatory disorder more generally, an immune disorder,autoimmune disorder, or complement Factor D related disease in a host,by providing an effective amount of a compound or pharmaceuticallyacceptable salt of an active compound or its salt or composition asdescribed herein to patient with a Factor D mediated inflammatorydisorder. An active compound or its salt or composition as describedherein as the only active agent or may be provided together with one ormore additional active agents.

In one embodiment, a method for the treatment of a disorder associatedwith a dysfunction in the complement cascade in a host is provided thatincludes the administration of an effective amount of an active compoundor its salt or composition as described herein. In one embodiment, amethod of inhibiting activation of the alternative complement pathway ina subject is provided that includes the administration of an effectiveamount of an active compound or its salt or composition as describedherein. In one embodiment, a method of modulating Factor D activity in asubject is provided that includes the administration of an effectiveamount of an active compound or its salt or composition as describedherein.

In an additional alternative embodiment, an active compound or its saltor composition as described herein is used in the treatment of anautoimmune disorder.

The complement pathway enhances the ability of antibodies and phagocyticcells to clear microbes and damaged cells from the body. It is part ofthe innate immune system and in healthy individuals is an essentialprocess. Inhibiting the complement pathway will decrease the body'simmune system response. Therefore, it is an object of the presentinvention to treat autoimmune disorders by administering an effectivedoes of an active compound or its salt or composition as describedherein to a subject in need thereof.

In one embodiment the autoimmune disorder is caused by activity of thecomplement system. In one embodiment the autoimmune disorder is causedby activity of the alternative complement pathway. In one embodiment theautoimmune disorder is caused by activity of the classical complementpathway. In another embodiment the autoimmune disorder is caused by amechanism of action that is not directly related to the complementsystem, such as the over-proliferation of T-lymphocytes or theover-production of cytokines.

Non-limiting examples of autoimmune disorders include: lupus, allograftrejection, autoimmune thyroid diseases (such as Graves' disease andHashimoto's thyroiditis), autoimmune uveoretinitis, giant cellarteritis, inflammatory bowel diseases (including Crohn's disease,ulcerative colitis, regional enteritis, granulomatous enteritis, distalileitis, regional ileitis, and terminal ileitis), diabetes, multiplesclerosis, pernicious anemia, psoriasis, rheumatoid arthritis,sarcoidosis, and scleroderma.

In one embodiment, an active compound or its salt or composition asdescribed herein is used in the treatment of lupus. Non-limitingexamples of lupus include lupus erythematosus, cutaneous lupus, discoidlupus erythematosus, chilblain lupus erythematosus, or lupuserythematosus-lichen planus overlap syndrome.

Lupus erythematosus is a general category of disease that includes bothsystemic and cutaneous disorders. The systemic form of the disease canhave cutaneous as well as systemic manifestations. However, there arealso forms of the disease that are only cutaneous without systemicinvolvement. For example, SLE is an inflammatory disorder of unknownetiology that occurs predominantly in women, and is characterized byarticular symptoms, butterfly erythema, recurrent pleurisy,pericarditis, generalized adenopathy, splenomegaly, as well as CNSinvolvement and progressive renal failure. The sera of most patients(over 98%) contain antinuclear antibodies, including anti-DNAantibodies. High titers of anti-DNA antibodies are essentially specificfor SLE. Conventional treatment for this disease has been theadministration of corticosteroids or immunosuppressants.

There are three forms of cutaneous lupus: chronic cutaneous lupus (alsoknown as discoid lupus erythematosus or DLE), subacute cutaneous lupus,and acute cutaneous lupus. DLE is a disfiguring chronic disorderprimarily affecting the skin with sharply circumscribed macules andplaques that display erythema, follicular plugging, scales,telangiectasia and atrophy. The condition is often precipitated by sunexposure, and the early lesions are erythematous, round scaling papulesthat are 5 to 10 mm in diameter and display follicular plugging. DLElesions appear most commonly on the cheeks, nose, scalp, and ears, butthey may also be generalized over the upper portion of the trunk,extensor surfaces of the extremities, and on the mucous membranes of themouth. If left untreated, the central lesion atrophies and leaves ascar. Unlike SLE, antibodies against double-stranded DNA (e.g.,DNA-binding test) are almost invariably absent in DLE.

Multiple Sclerosis is an autoimmune demyelinating disorder that isbelieved to be T lymphocyte dependent. MS generally exhibits arelapsing-remitting course or a chronic progressive course. The etiologyof MS is unknown, however, viral infections, genetic predisposition,environment, and autoimmunity all appear to contribute to the disorder.Lesions in MS patients contain infiltrates of predominantly T lymphocytemediated microglial cells and infiltrating macrophages. CD4+ Tlymphocytes are the predominant cell type present at these lesions. Thehallmark of the MS lesion is plaque, an area of demyelination sharplydemarcated from the usual white matter seen in MRI scans. Histologicalappearance of MS plaques varies with different stages of the disease. Inactive lesions, the blood-brain barrier is damaged, thereby permittingextravasation of serum proteins into extracellular spaces. Inflammatorycells can be seen in perivascular cuffs and throughout white matter.CD4+ T-cells, especially Th1, accumulate around postcapillary venules atthe edge of the plaque and are also scattered in the white matter. Inactive lesions, up-regulation of adhesion molecules and markers oflymphocyte and monocyte activation, such as IL2-R and CD26 have alsobeen observed. Demyelination in active lesions is not accompanied bydestruction of oligodendrocytes. In contrast, during chronic phases ofthe disease, lesions are characterized by a loss of oligodendrocytes andhence, the presence of myelin oligodendrocyte glycoprotein (MOG)antibodies in the blood.

Diabetes can refer to either type 1 or type 2 diabetes. In oneembodiment an active compound or its salt or composition as describedherein is provided at an effective dose to treat a patient with type 1diabetes. In one embodiment an active compound or its salt orcomposition as described herein is provided at an effective dose totreat a patient with type 2 diabetes.

Type 1 diabetes is an autoimmune disease. An autoimmune disease resultswhen the body's system for fighting infection (the immune system) turnsagainst a part of the body. The pancreas then produces little or noinsulin.

V. Combination Therapy

In one embodiment an active compound or its salt or composition asdescribed herein may be provided in combination or alternation with orpreceded by, concomitant with or followed by, an effective amount of atleast one additional therapeutic agent, for example, for treatment of adisorder listed herein. Non-limiting examples of second active agentsfor such combination therapy are provided below.

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination or alternation with atleast one additional inhibitor of the complement system or a secondactive compound with a different biological mechanism of action. In thedescription below and herein generally, whenever any of the termsreferring to an active compound or its salt or composition as describedherein are used, it should be understood that pharmaceuticallyacceptable salts, prodrugs or compositions are considered included,unless otherwise stated or inconsistent with the text.

In non-limiting embodiments, an active compound or its salt orcomposition as described herein may be provided together with a proteaseinhibitor, a soluble complement regulator, a therapeutic antibody(monoclonal or polyclonal), complement component inhibitor, receptoragonist, or siRNA.

In other embodiments, an active compound described herein isadministered in combination or alternation with an antibody againsttumor necrosis factor (TNF), including but not limited to infliximab(Remicade), adalimumab, certolizumab, golimumab, or a receptor fusionprotein such as etanercept (Embrel).

In another embodiment, an active compound as described herein can beadministered in combination or alternation with an anti-CD20 antibody,including but not limited to rituximab (Rituxan), adalimumab (Humira),ofatumumab (Arzerra), tositumomab (Bexxar), obinutuzumab (Gazyva), oribritumomab (Zevalin).

In an alternative embodiment, an active compound as described herein canbe administered in combination or alternation with an anti-IL6 antibody,including but not limited to tocilizumab (Actemra) and siltuximab(Sylvant).

In an alternative embodiment, an active compound as described herein canbe administered in combination or alternation with an IL17 inhibitor,including but not limited to secukibumab (Cosentyx).

In an alternative embodiment, an active compound as described herein canbe administered in combination or alternation with a p40 (IL12/IL23)inhibitor, including but not limited to ustekinumab (Stelara).

In an alternative embodiment, an active compound as described herein canbe administered in combination or alteration with an TL23 inhibitor,including but not limited to risankizumab.

In an alternative embodiment, an active compound as described herein canbe administered in combination or alteration with an anti-interferon αantibody, for example but not limited to sifalimumab.

In an alternative embodiment, an active compound as described herein canbe administered in combination or alteration with a kinase inhibitor,for example but not limited to a JAK1/JAK3 inhibitor, for example butnot limited to tofacitinib (Xelianz). In an alternative embodiment, anactive compound as described herein can be administered in combinationor alteration with a JAK1/JAK2 inhibitor, for example but not limited tobaracitibib.

In another embodiment, an active compound as described herein can beadministered in combination or alternation with an immune checkpointinhibitor. Non-limiting examples of checkpoint inhibitors are anti-PD-1or anti-PDL1 antibodies (for example, Nivolumab, Pembrolizumab,Pidilizumab and Atezolizumab) and anti-CTLA4 antibodies (Ipilimumab andTremelimumab).

Non-limiting examples of active agents that can be used in combinationwith active compounds described herein are:

Protease inhibitors: plasma-derived C1-INH concentrates, for exampleCetor® (Sanquin), Berinert-P® (CSL Behring, Lev Pharma), and Cinryze®;recombinant human C1-inhibitors, for example Rhucin®; ritonavir(Norvir®, Abbvie, Inc.);

Soluble complement regulators: Soluble complement receptor 1 (TP10)(Avant Immunotherapeutics); sCR1-sLe^(X)/TP-20 (AvantImmunotherapeutics); MLN-2222/CAB-2 (Millenium Pharmaceuticals);Mirococept (Inflazyme Pharmaceuticals);

Therapeutic antibodies: Eculizumab/Soliris (Alexion Pharmaceuticals);Pexelizumab (Alexion Pharmaceuticals); Ofatumumab (Genmab A/S); TNX-234(Tanox); TNX-558 (Tanox); TA106 (Taligen Therapeutics); Neutrazumab (G2Therapies); Anti-properdin (Novelmed Therapeutics); HuMax-CD38 (GenmabA/S);

Complement component inhibitors: Compstatin/POT-4 (PotentiaPharmaceuticals); ARC1905 (Archemix);

Receptor agonists: PMX-53 (Peptech Ltd.); JPE-137 (Jerini); JSM-7717(Jerini);

Others: Recombinant human MBL (rhMBL; Enzon Pharmaceuticals);

Imides and glutarimide derivatives such as thalidomide, lenalidomide,pomalidomide;

Additional non-limiting examples that can be used in combination oralternation with an active compound or its salt or composition asdescribed herein include the following.

Non-limiting examples of potential therapeutics for combination therapyName Target Company Class of Molecule LFG316 C5 Novartis/MorphosysMonoclonal antibody 4(1MEW)APL-1, APL-2 C3/C3b Apella Compstatin Family4(1MeW)POT-4 C3/C3b Potentia Compstatin Family Anti-C5 siRNA C5 AlnylamSi-RNA Anti-FB siRNA CFB Alnylam SiRNA ARC1005 C5 Novo Nordisk AptamersATA C5 N.A. Chemical Coversin C5 Volution Immuno- Small animal proteinPharmaceuticals CP40/AMY-101, PEG- C3/C3b Amyndas Compstatin Family Cp40CRIg/CFH CAP C3 NA CFH-based protein convertase Cynryze C1n/C1sViroPharma/Baxter Human purified protein FCFD4514S CFD Genentech/RocheMonoclonal antibody H17 C3 EluSys Therapeutics Monoclonal antibody(C3b/iC3b) Mini-CFH CAP C3 Amyndas CFH-based protein convertaseMirococept (APT070) CAP and NA CR1-based protein CCP C3 Mubodine C5Adienne Monoclonal antibody RA101348 C5 Rapharma Small molecule sCR1(CDX-1135) CAP and CP Celldex CR1-based protein C3 SOBI002 C5 SwedishOrphan Affibody Biovitrum SOMAmers C5 SomaLogic Aptamers SOMAmers CFBand SomaLogic Aptamers (SELEX) CFD TA106 CFB Alexion Monoclonal antibodyPharmaceuticals TNT003 C1s True North Monoclonal antibody TT30 (CR2/CFH)CAP C3 Alexion CFH-based protein convertase TT32 (CR2/CR1) CAP and CCPAlexion CR1-based protein C3 Pharmaceuticals Nafamostat (FUT-175, C1s,CFD, Torri Pharmaceuticals Small molecule Futhan) other proteases OMS721MASP-2 Omeros Monoclonal antibody OMS906 MASP-3 Omeros Monoclonalantibody Bikaciomab, NM9308 CFB Novelmed Monoclonal antibody NM9401Properdin Novelmed Monoclonal antibody CVF, HC-1496 C3 InCodeRecombinant peptide ALXN1102/ALXN1103 C3-conv, C3b Alexion Regulator(TT30) Pharmaceuticals rFH C3-conv, C3b Optherion Regulator 5C6, AMY-301CFH Amyndas Regulator Erdigna C5 Adienne Pharma Antibody ARC1905 C5Opthotech Monoclonal Antibody MEDI7814 C5/C5a MedImmune MonoclonalAntibody NOX-D19 C5a Noxxon Aptamer (Spiegelmer) IFX-1, CaCP29 C5aInflaRx Monoclonal Antibody PMX53, PMX205 C5aR Cephalon, TevaPeptidomimetic CCX168 C5aR ChemoCentryx Small molecule ADC-1004 C5aRAlligator Bioscience Small molecule Anti-C5aR-151, C5aR Novo NordiskMonoclonal Antibody NN8209; Anti-C5aR- 215, NN8210 Imprime PGG CR3Biothera Soluble beta-glucan

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided together with a compound that inhibitsan enzyme that metabolizes an administered protease inhibitor. In oneembodiment, a compound or salt may be provided together with ritonavir.

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with a complement C5inhibitor or C5 convertase inhibitor. In another embodiment, an activecompound or its salt or composition as described herein may be providedin combination with eculizumab, a monoclonal antibody directed to thecomplement factor C5 and manufactured and marketed by AlexionPharmaceuticals under the tradename Soliris. Eculizumab has beenapproved by the U.S. FDA for the treatment of PNH and aHUS.

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided together with a compound that inhibitscomplement factor D. In one embodiment of the invention, an activecompound or its salt or composition as described herein as describedherein can be used in combination or alternation with a compounddescribed in Biocryst Pharmaceuticals U.S. Pat. No. 6,653,340 titled“Compounds useful in the complement, coagulate and kallikrein pathwaysand method for their preparation” describes fused bicyclic ringcompounds that are potent inhibitors of Factor D; Novartis PCT patentpublication WO2012/093101 titled “Indole compounds or analogues thereofuseful for the treatment of age-related macular degeneration” describescertain Factor D inhibitors; Novartis PCT patent publicationsWO2014/002051, WO2014/002052, WO2014/002053, WO2014/002054,WO2014/002057, WO2014/002058, WO2014/002059, WO2014/005150,WO2014/009833, WO 2013/164802, WO 2015/009616, WO 2015/066241,Bristol-Myers Squibb PCT patent publication WO2004/045518 titled “Openchain prolyl urea-related modulators of androgen receptor function”;Japan Tobacco Inc. PCT patent publication WO1999/048492 titled “Amidederivatives and nociceptin antagonists”; Ferring B. V. and YamanouchiPharmaceutical Co. LTD. PCT patent publication WO1993/020099 titled “CCKand/or gastrin receptor ligands”; Alexion Pharmaceuticals PCT patentpublication WO1995/029697 titled “Methods and compositions for thetreatment of glomerulonephritis and other inflammatory diseases”; orAchillion Pharmaceuticals filed PCT Patent Application No.PCT/US2015/017523 and U.S. patent application Ser. No. 14/631,090 titled“Alkyne Compounds for Treatment of Complement Mediated Disorders”; PCTPatent Application No. PCT/US2015/017538 and U.S. patent applicationSer. No. 14/631,233 titled “Amide Compounds for Treatment of ComplementMediated Disorders”; PCT Patent Application No. PCT/US2015/017554 andU.S. patent application Ser. No. 14/631,312 titled “Amino Compounds forTreatment of Complement Mediated Disorders”; PCT Patent Application No.PCT/US2015/017583 and U.S. patent application Ser. No. 14/631,440 titled“Carbamate, Ester, and Ketone Compounds for Treatment of ComplementMediated Disorders”; PCT Patent Application No. PCT/US2015/017593 andU.S. patent application Ser. No. 14/631,625 titled “Aryl, Heteroaryl,and Heterocyclic Compounds for Treatment of Complement MediatedDisorders”; PCT Patent Application No. PCT/US2015/017597 and U.S. patentapplication Ser. No. 14/631,683 titled “Ether Compounds for Treatment ofComplement Mediated Disorders”; PCT Patent Application No.PCT/US2015/017600 and U.S. patent application Ser. No. 14/631,785 titled“Phosphonate Compounds for Treatment of Complement Mediated Disorders”;and PCT Patent Application No. PCT/US2015/017609 and U.S. patentapplication Ser. No. 14/631,828 titled “Compounds for Treatment ofComplement Mediated Disorders.”

In one embodiment, an active compound or its salt or composition asdescribed herein is administered in combination with ananti-inflammatory drug, antimicrobial agent, anti-angiogenesis agent,immunosuppressant, antibody, steroid, ocular antihypertensive drug orcombinations thereof. Examples of such agents include amikacin,anecortane acetate, anthracenedione, anthracycline, an azole,amphotericin B, bevacizumab, camptothecin, cefuroxime, chloramphenicol,chlorhexidine, chlorhexidine digluconate, clortrimazole, a clotrimazolecephalosporin, corticosteroids, dexamethasone, desamethazone, econazole,eftazidime, epipodophyllotoxin, fluconazole, flucytosine,fluoropyrimidines, fluoroquinolines, gatifloxacin, glycopeptides,imidazoles, itraconazole, ivermectin, ketoconazole, levofloxacin,macrolides, miconazole, miconazole nitrate, moxifloxacin, natamycin,neomycin, nystatin, ofloxacin, polyhexamethylene biguanide,prednisolone, prednisolone acetate, pegaptanib, platinum analogues,polymicin B, propamidine isethionate, pyrimidine nucleoside,ranibizumab, squalamine lactate, sulfonamides, triamcinolone,triamcinolone acetonide, triazoles, vancomycin, anti-vascularendothelial growth factor (VEGF) agents, VEGF antibodies, VEGF antibodyfragments, vinca alkaloid, timolol, betaxolol, travoprost, latanoprost,bimatoprost, brimonidine, dorzolamide, acetazolamide, pilocarpine,ciprofloxacin, azithromycin, gentamycin, tobramycin, cefazolin,voriconazole, gancyclovir, cidofovir, foscarnet, diclofenac, nepafenac,ketorolac, ibuprofen, indomethacin, fluoromethalone, rimexolone,anecortave, cyclosporine, methotrexate, tacrolimus and combinationsthereof.

In one embodiment of the present invention, an active compound or itssalt or composition as described herein can be administered incombination or alternation with at least one immunosuppressive agent.The immunosuppressive agent as non-limiting examples, may be acalcineurin inhibitor, e.g. a cyclosporin or an ascomycin, e.g.Cyclosporin A (NEORAL®), FK506 (tacrolimus), pimecrolimus, a mTORinhibitor, e.g. rapamycin or a derivative thereof, e.g. Sirolimus(RAPAMUNE), Everolimus (Certican®), temsirolimus, zotarolimus,biolimus-7, biolimus-9, a rapalog, e.g. ridaforolimus, azathioprine,campath 1H, a S1P receptor modulator, e.g. fingolimod or an analoguethereof, an antiIL-8 antibody, mycophenolic acid or a salt thereof, e.g.sodium salt, or a prodrug thereof, e.g. Mycophenolate Mofetil(CELLCEPT®), OKT3 (ORTHOCLONE OKT3®), Prednisone, ATGAM®,THYMOGLOBULIN®, Brequinar Sodium, OKT4, T10B9.A-3A, 33B3.1,15-deoxyspergualin, tresperimus, Leflunomide ARAVA®, CTLAI-Ig,anti-CD25, anti-IL2R, Basiliximab (SIMULECT®), Daclizumab (ZENAPAX®),mizorbine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981(pimecrolimus, Elidel®), CTLA41g (Abatacept), belatacept, LFA31g,etanercept (sold as Enbrel® by Immunex), adalimumab (Humira®),infliximab (Remicade®), an anti-LFA-1 antibody, natalizumab (Antegren®),Enlimomab, gavilimomab, antithymocyte immunoglobulin, siplizumab,Alefacept efalizumab, pentasa, mesalazine, asacol, codeine phosphate,benorylate, fenbufen, naprosyn, diclofenac, etodolac and indomethacin,tocilizumab (Actemra), siltuximab (Sylvant), secukibumab (Cosentyx),ustekinumab (Stelara), risankizumab, sifalimumab, aspirin and ibuprofen.

Examples of anti-inflammatory agents include methotrexate,dexamethasone, dexamethasone alcohol, dexamethasone sodium phosphate,fluromethalone acetate, fluromethalone alcohol, lotoprendol etabonate,medrysone, prednisolone acetate, prednisolone sodium phosphate,difluprednate, rimexolone, hydrocortisone, hydrocortisone acetate,lodoxamide tromethamine, aspirin, ibuprofen, suprofen, piroxicam,meloxicam, flubiprofen, naproxan, ketoprofen, tenoxicam, diclofenacsodium, ketotifen fumarate, diclofenac sodium, nepafenac, bromfenac,flurbiprofen sodium, suprofen, celecoxib, naproxen, rofecoxib,glucocorticoids, diclofenac, and any combination thereof. In oneembodiment, an active compound or its salt or composition as describedherein is combined with one or more non-steroidal anti-inflammatorydrugs (NSAIDs) selected from naproxen sodium (Anaprox), celecoxib(Celebrex), sulindac (Clinoril), oxaprozin (Daypro), salsalate(Disalcid), diflunisal (Dolobid), piroxicam (Feldene), indomethacin(Indocin), etodolac (Lodine), meloxicam (Mobic), naproxen (Naprosyn),nabumetone (Relafen), ketorolac tromethamine (Toradol),naproxen/esomeprazole (Vimovo), and diclofenac (Voltaren), andcombinations thereof.

In one embodiment, an active compound or its salt or composition asdescribed herein is administered in combination or alteration with anomega-3 fatty acid or a peroxisome proliferator-activated receptor(PPARs) agonist. Omega-3 fatty acids are known to reduce serumtriglycerides by inhibiting DGAT and by stimulating peroxisomal andmitochondrial beta oxidation. Two omega-3 fatty acids, eicosapentaenoicacid (EPA) and docosahexaenoic acid (DHA), have been found to have highaffinity for both PPAR-alpha and PPAR-gamma. Marine oils, e.g., fishoils, are a good source of EPA and DHA, which have been found toregulate lipid metabolism. Omega-3 fatty acids have been found to havebeneficial effects on the risk factors for cardiovascular diseases,especially mild hypertension, hypertriglyceridemia and on thecoagulation factor VII phospholipid complex activity. Omega-3 fattyacids lower serum triglycerides, increase serum HDL-cholesterol, lowersystolic and diastolic blood pressure and the pulse rate, and lower theactivity of the blood coagulation factor VII-phospholipid complex.Further, omega-3 fatty acids seem to be well tolerated, without givingrise to any severe side effects. One such form of omega-3 fatty acid isa concentrate of omega-3, long chain, polyunsaturated fatty acids fromfish oil containing DHA and EPA and is sold under the trademark Omacor®.Such a form of omega-3 fatty acid is described, for example, in U.S.Pat. Nos. 5,502,077, 5,656,667 and 5,698,594, the disclosures of whichare incorporated herein by reference.

Peroxisome proliferator-activated receptors (PPARs) are members of thenuclear hormone receptor superfamily ligand-activated transcriptionfactors that are related to retinoid, steroid and thyroid hormonereceptors. There are three distinct PPAR subtypes that are the productsof different genes and are commonly designated PPAR-alpha,PPAR-beta/delta (or merely, delta) and PPAR-gamma. General classes ofpharmacological agents that stimulate peroxisomal activity are known asPPAR agonists, e.g., PPAR-alpha agonists, PPAR-gamma agonists andPPAR-delta agonists. Some pharmacological agents are combinations ofPPAR agonists, such as alpha/gamma agonists, etc., and some otherpharmacological agents have dual agonist/antagonist activity. Fibratessuch as fenofibrate, bezafibrate, clofibrate and gemfibrozil, arePPAR-alpha agonists and are used in patients to decrease lipoproteinsrich in triglycerides, to increase HDL and to decrease atherogenic-denseLDL. Fibrates are typically orally administered to such patients.Fenofibrate or 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid,1-methylethyl ester, has been known for many years as a medicinallyactive principle because of its efficacy in lowering blood triglycerideand cholesterol levels.

In one embodiment, the present invention provides a method of treatingor preventing age-related macular degeneration (AMD) by administering toa subject in need thereof an effective amount of an active compound orits salt or composition as described herein in combination with ananti-VEGF agent. Non-limiting examples of anti-VEGF agents include, butare not limited to, aflibercept (Eylea®; Regeneron Pharmaceuticals);ranibizumab (Lucentis®: Genentech and Novartis); and pegaptanib(Macugen®; OSI Pharmaceuticals and Pfizer); Bevacizumab (Avastin;Genentech/Roche); anecortane acetate, squalamine lactate, andcorticosteroids, including, but not limited to, triamcinolone acetonide.

In one embodiment, the present invention provides a method of treatingor preventing paroxysmal nocturnal hemoglobinuria (PNH) by administeringto a subject in need thereof an effective amount of an active compoundor its salt or composition as described herein with an additionalinhibitor of the complement system or another active compound with adifferent biological mechanism of action. In another embodiment, thepresent invention provides a method of treating or preventing paroxysmalnocturnal hemoglobinuria (PNH) by administering to a subject in needthereof an effective amount of an active compound or its salt orcomposition as described herein in combination or alternation witheculizumab. In another embodiment, the present invention provides amethod of treating or preventing paroxysmal nocturnal hemoglobinuria(PNH) by administering to a subject in need thereof an effective amountof an active compound or its salt or composition as described herein incombination or alternation with CP40. In one embodiment, the additionalagent is PEGylated-CP40. CP40 is a peptide inhibitor that shows a strongbinding affinity for C3b and inhibits hemolysis of paroxysmal nocturnalhemoglobinuria (PNH) erythrocytes.

In one embodiment, the present invention provides a method of treatingor preventing rheumatoid arthritis by administering to a subject in needthereof an effective amount of a composition comprising an activecompound or its salt or composition as described herein in combinationor alternation with an additional inhibitor of the complement system, oran active agent that functions through a different mechanism of action.In another embodiment, the present invention provides a method oftreating or preventing rheumatoid arthritis by administering to asubject in need thereof an effective amount of an active compound or itssalt or composition as described herein in combination or alternationwith methotrexate. In certain embodiments, an active compound or itssalt or composition as described herein is administered in combinationor alternation with at least one additional therapeutic agent selectedfrom: salicylates including aspirin (Anacin, Ascriptin, Bayer Aspirin,Ecotrin) and salsalate (Mono-Gesic, Salgesic); nonsteroidalanti-inflammatory drugs (NSAIDs); nonselective inhibitors of thecyclo-oxygenase (COX-1 and COX-2) enzymes, including diclofenac(Cataflam, Voltaren), ibuprofen (Advil, Motrin), ketoprofen (Orudis),naproxen (Aleve, Naprosyn), piroxicam (Feldene), etodolac (Lodine),indomethacin, oxaprozin (Daypro), nabumetone (Relafen), and meloxicam(Mobic); selective cyclo-oxygenase-2 (COX-2) inhibitors includingCelecoxib (Celebrex); disease-modifying antirheumatic drugs (DMARDs),including azathioprine (Imuran), cyclosporine (Sandimmune, Neoral), goldsalts (Ridaura, Solganal, Aurolate, Myochrysine), hydroxychloroquine(Plaquenil), leflunomide (Arava), methotrexate (Rheumatrex),penicillamine (Cuprimine), and sulfasalazine (Azulfidine); biologicdrugs including abatacept (Orencia), etanercept (Enbrel), infliximab(Remicade), adalimumab (Humira), and anakinra (Kineret); corticosteroidsincluding betamethasone (Celestone Soluspan), cortisone (Cortone),dexamethasone (Decadron), methylprednisolone (SoluMedrol, DepoMedrol),prednisolone (Delta-Cortef), prednisone (Deltasone, Orasone), andtriamcinolone (Aristocort); gold salts, including Auranofin (Ridaura);Aurothioglucose (Solganal); Aurolate; Myochrysine; or any combinationthereof.

In one embodiment, the present invention provides a method of treatingor preventing multiple sclerosis by administering to a subject in needthereof an effective amount of an active compound or its salt orcomposition as described herein in combination or alternation with anadditional inhibitor of the complement system, or an active agent thatfunctions through a different mechanism of action. In anotherembodiment, the present invention provides a method of treating orpreventing multiple sclerosis by administering to a subject in needthereof an effective amount of an active compound or its salt orcomposition as described herein in combination or alternation with acorticosteroid. Examples of corticosteroids include, but are not limitedto, prednisone, dexamethasone, solumedrol, and methylprednisolone. Inone embodiment, an active compound or its salt or composition asdescribed herein is combined with at least one anti-multiple sclerosisdrug, for example, selected from: Aubagio (teriflunomide), Avonex(interferon beta-1a), Betaseron (interferon beta-1b), Copaxone(glatiramer acetate), Extavia (interferon beta-1b), Gilenya(fingolimod), Lemtrada (alemtuzumab), Novantrone (mitoxantrone),Plegridy (peginterferon beta-1a), Rebif (interferon beta-1a), Tecfidera(dimethyl fumarate), Tysabri (natalizumab), Solu-Medrol(methylprednisolone), High-dose oral Deltasone (prednisone), H. P.Acthar Gel (ACTH), or a combination thereof.

In one embodiment, an active compound or its salt or composition asdescribed herein is useful in a combination with another pharmaceuticalagent to ameliorate or reduce a side effect of the agent. For example,in one embodiment, an active compound or its salt or composition asdescribed herein may be used in combination with adoptive cell transfertherapies to reduce an associated inflammatory response associated withsuch therapies, for example, a cytokine mediated response such ascytokine release syndrome. In one embodiment, the adoptive cell transfertherapy includes the use of a chimeric antigen receptor T-Cell (CAR T).In one embodiment, the adoptive cell transfer therapy includes the useof a chimeric antigen receptor T-Cell (CAR T) or a dendritic cell totreat a hematologic or solid tumor, for example, a B-cell relatedhematologic cancer. In one embodiment, the hematologic or solid tumor isacute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML),non-Hodgkin's lymphoma, chronic lymphocytic leukemia (CLL), pancreaticcancer, glioblastoma, or a cancer that expresses CD19.

In an additional alternative embodiment, an active compound or its saltor composition as described herein may be provided in combination witheculizumab for the treatment of PNH, aHUSs, STEC-HUS, ANCA-vasculitis,AMD, CAD, chronic hemolysis, neuromyelitis optica, or transplantationrejection. In one embodiment, an active compound or its salt orcomposition as described herein may be provided in combination withcompstatin or a compstatin derivative for the treatment of PNH, aHUSs,STEC-HUS, ANCA-vasculitis, AMD, CAD, chronic hemolysis, neuromyelitisoptica, or transplantation rejection.

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with rituxan for thetreatment of a complement mediated disorder. In one embodiment, thecomplement mediated disorder is, for example, rheumatoid arthritis,Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis), andMicroscopic Polyangiitis (MPA). In one embodiment, the disorder isLupus.

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with cyclophosphamidefor the treatment of a complement mediated disorder. In one embodiment,the disorder is an autoimmune disease. In one embodiment, the complementmediated disorder is, for example, rheumatoid arthritis, Granulomatosiswith Polyangiitis (GPA) (Wegener's Granulomatosis), and MicroscopicPolyangiitis (MPA). In one embodiment, the disorder is Lupus.

In one embodiment, an active compound or its salt or composition asdescribed herein is dosed in combination with a conventional DLEtreatment for the treatment of lupus to a subject in need thereof.

Examples of conventional DLE treatments include topical corticosteroidointments or creams, such as triamcinolone acetonide, fluocinolone,flurandrenolide, betamethasone valerate, or betamethasone dipropionate.Resistant plaques can be injected with an intradermal corticosteroid.Other potential DLE treatments include calcineurin inhibitors such aspimecrolimus cream or tacrolimus ointment. Particularly resistant casescan be treated with systemic antimalarial drugs, such ashydroxychloroquine (PLAQUENIL).

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with methotrexate forthe treatment of Lupus.

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with azathioprine forthe treatment of Lupus.

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with a non-steroidalanti-inflammatory drug for the treatment of Lupus.

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with a corticosteroidfor the treatment of Lupus.

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with a belimumab(Benlysta) for the treatment of Lupus.

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with hydroxychloroquine(Plaquenil) for the treatment of Lupus.

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with sifalimumab for thetreatment of Lupus.

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with OMS721 (Omeros) forthe treatment of a complement mediated disorder. In one embodiment, anactive compound or its salt or composition as described herein may beprovided in combination with OMS906 (Omeros) for the treatment of acomplement mediated disorder. In one embodiment, the complement mediateddisorder is, for example, thrombotic thrombocytopenic purpura (TTP) oraHUS.

In one embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with ananti-inflammatory agent, immunosuppressive agent, or anti-cytokine agentfor the treatment or prevention of cytokine or inflammatory reactions inresponse to the administration of pharmaceuticals or biotherapeutics(e.g. adoptive T-cell therapy (ACT) such as CAR T-cell therapy, ormonoclonal antibody therapy). In one embodiment, an active compound orits salt or composition as described herein may be provided incombination with a corticosteroid, for example prednisone,dexamethasone, solumedrol, and methylprednisolone, and/or anti-cytokinecompounds targeting, e.g., IL-4, IL-10, IL-11, IL-13 and TGFβ. In oneembodiment, an active compound or its salt or composition as describedherein may be provided in combination with an anti-cytokine inhibitorincluding, but are not limited to, adalimumab, infliximab, etanercept,protopic, efalizumab, alefacept, anakinra, siltuximab, secukibumab,ustekinumab, golimumab, and tocilizumab, or a combination thereof.Additional anti-inflammatory agents that can be used in combination withan active compound or its salt or composition as described hereininclude, but are not limited to, non-steroidal anti-inflammatory drug(s)(NSAIDs); cytokine suppressive anti-inflammatory drug(s) (CSAIDs);CDP-571/BAY-10-3356 (humanized anti-TNFα antibody; Celltech/Bayer);cA2/infliximab (chimeric anti-TNFα antibody; Centocor); 75kdTNFR-IgG/etanercept (75 kD TNF receptor-IgG fusion protein; Immunex);55 kdTNF-IgG (55 kD TNF receptor-IgG fusion protein; Hoffmann-LaRoche);IDEC-CE9.1/SB 210396 (non-depleting primatized anti-CD4 antibody;IDEC/SmithKline); DAB 486-IL-2 and/or DAB 389-IL-2 (IL-2 fusionproteins; Seragen); Anti-Tac (humanized anti-IL-2Rα; Protein DesignLabs/Roche); IL-4 (anti-inflammatory cytokine; DNAX/Schering); IL-10(SCH 52000; recombinant IL-10, anti-inflammatory cytokine;DNAX/Schering); IL-4; IL-10 and/or IL-4 agonists (e.g., agonistantibodies); IL-1RA (IL-1 receptor antagonist; Synergen/Amgen); anakinra(Kineret®/Amgen); TNF-bp/s-TNF (soluble TNF binding protein); R973401(phosphodiesterase Type IV inhibitor); MK-966 (COX-2 Inhibitor);Iloprost, leflunomide (anti-inflammatory and cytokine inhibition);tranexamic acid (inhibitor of plasminogen activation); T-614 (cytokineinhibitor); prostaglandin E1; Tenidap (non-steroidal anti-inflammatorydrug); Naproxen (non-steroidal anti-inflammatory drug); Meloxicam(non-steroidal anti-inflammatory drug); Ibuprofen (non-steroidalanti-inflammatory drug); Piroxicam (non-steroidal anti-inflammatorydrug); Diclofenac (non-steroidal anti-inflammatory drug); Indomethacin(non-steroidal anti-inflammatory drug); Sulfasalazine; Azathioprine; ICEinhibitor (inhibitor of the enzyme interleukin-1 converting enzyme);zap-70 and/or lck inhibitor (inhibitor of the tyrosine kinase zap-70 orlck); TNF-convertase inhibitors; anti-IL-12 antibodies; anti-IL-18antibodies; interleukin-11; interleukin-13; interleukin-17 inhibitors;gold; penicillamine; chloroquine; chlorambucil; hydroxychloroquine;cyclosporine; cyclophosphamide; anti-thymocyte globulin; anti-CD4antibodies; CD5-toxins; orally-administered peptides and collagen;lobenzarit disodium; Cytokine Regulating Agents (CRAB) HP228 and HP466(Houghten Pharmaceuticals, Inc.); ICAM-1 antisense phosphorothioateoligo-deoxynucleotides (ISIS 2302; Isis Pharmaceuticals, Inc.); solublecomplement receptor 1 (TP10; T Cell Sciences, Inc.); prednisone;orgotein; glycosaminoglycan polysulphate; minocycline; anti-IL2Rantibodies; marine and botanical lipids (fish and plant seed fattyacids); auranofin; phenylbutazone; meclofenamic acid; flufenamic acid;intravenous immune globulin; zileuton; azaribine; mycophenolic acid(RS-61443); tacrolimus (FK-506); sirolimus (rapamycin); amiprilose(therafectin); cladribine (2-chlorodeoxyadenosine).

In a specific embodiment, an active compound or its salt or compositionas described herein may be provided in combination with a corticosteroidfor the treatment or prevention of cytokine or inflammatory reactions inresponse to the administration of pharmaceuticals or biotherapeutics. Inanother embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with etarnercept for thetreatment or prevention of cytokine or inflammatory reactions inresponse to the administration of pharmaceuticals or biotherapeutics. Inanother embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with tocilizumab for thetreatment or prevention of cytokine or inflammatory reactions inresponse to the administration of pharmaceuticals or biotherapeutics. Inanother embodiment, an active compound or its salt or composition asdescribed herein may be provided in combination with etarnercept andtocilizumab for the treatment or prevention of cytokine or inflammatoryreactions in response to the administration of pharmaceuticals orbiotherapeutics. In another embodiment, an active compound or its saltor composition as described herein may be provided in combination withinfliximab for the treatment or prevention of cytokine or inflammatoryreactions in response to the administration of pharmaceuticals orbiotherapeutics. In another embodiment, an active compound or its saltor composition as described herein may be provided in combination withgolimumab for the treatment or prevention of cytokine or inflammatoryreactions in response to the administration of pharmaceuticals orbiotherapeutics.

VI. Combinations for Prophylactic or Concommitant Anti-Bacterial Therapy

In one aspect of the present invention, a method is provided fortreating a host in need thereof that comprises administering aneffective amount of a prophylactic anti-bacterial vaccine prior toadministration of an active compound or its salt or composition for anyof the disorders described herein. In another aspect of the presentinvention, a method is provided for treating a host in need thereof thatcomprises administering an effective amount of a prophylacticanti-bacterial drug, such as a pharmaceutical drug, prior toadministration of an active compound or its salt or composition for anyof the disorders described herein. In one aspect of the presentinvention, a method is provided for treating a host in need thereof thatcomprises administering an effective amount of an anti-bacterial vaccineafter administration of an active compound or its salt or compositionfor any of the disorders described herein. In another aspect of thepresent invention, a method is provided for treating a host in needthereof that comprises administering an effective amount of ananti-bacterial drug, such as a pharmaceutical drug, after administrationof an active compound or its salt or composition for any of thedisorders described herein. In one embodiment, the disorder is PNH oraHUS. In one embodiment, the host has received an organ or other tissueor biological fluid transplant. In one embodiment, the host is alsoadministered eculizumab.

In one aspect of the present invention, an active compound or its saltor composition as described herein is administered to a hostconcomitantly to a subject following the prophylactic administration ofa vaccine against a bacterial infection. In one embodiment, thecomplement mediated disorder is PNH or aHUS. In one embodiment, thesubject has received an organ or other tissue or biological fluidtransplant. In one embodiment, the subject is also administeredeculizumab.

In one aspect of the present invention, an active compound or its saltor composition as described herein is administered to a subjectconcomitantly with the prophylactic administration of a vaccine againsta bacterial infection. In one embodiment, the complement mediateddisorder is PNH or aHUS. In one embodiment, the subject has received anorgan or other tissue or biological fluid transplant. In one embodiment,the subject is also administered eculizumab.

In one aspect of the present invention, an active compound or its saltor composition as described herein is administered to a subject and,during the administration period of the compound or salt, a vaccineagainst a bacterial infection is administered to the subject. In oneembodiment, the complement mediated disorder is PNH or aHUS. In oneembodiment, the subject has received an organ or other tissue orbiological fluid transplant. In one embodiment, the subject is alsoadministered eculizumab.

In one aspect of the present invention, the subject is administered anactive compound or its salt or composition as described herein incombination with an antibiotic compound for the duration of factor Dinhibitor administration. In one embodiment, the complement mediateddisorder is PNH or aHUS. In one embodiment, the subject has received anorgan or other tissue or biological fluid transplant. In one embodiment,the subject is also administered eculizumab.

In one aspect of the present invention, an active compound or its saltor composition as described herein is administered to a subjectfollowing the prophylactic administration of a vaccine against abacterial infection, and in combination with an antibiotic compound forthe duration of factor D inhibitor administration. In one embodiment,the complement mediated disorder is PNH or aHUS. In one embodiment, thesubject has received an organ or other tissue or biological fluidtransplant. In one embodiment, the subject is also administeredeculizumab.

In one embodiment, the subject, prior to receiving an active compound orits salt or composition as described herein, is vaccinated against abacterial infection caused by the bacterium Neisseria meningitidis. Inone embodiment, the subject is vaccinated against a bacterial infectioncaused by the bacterium Haemophilus influenzae. In one embodiment, theHaemophilus influenzae is Haemophilus influenzae serotype B (Hib). Inone embodiment, the subject is vaccinated against a bacterial infectioncaused by Streptococcus pneumoniae. In one embodiment, the subject isvaccinated against a bacterial infection caused by the bacteriumNeisseria meningitidis, Haemophilus influenzae, or Streptococcuspneumoniae, or a combination of one or more of Neisseria meningitidis,Haemophilus influenzae, or Streptococcus pneumoniae. In one embodiment,the subject is vaccinated against a bacterial infection caused by thebacterium Neisseria meningitidis, Haemophilus influenzae, andStreptococcus pneumoniae.

In other embodiments, the subject is vaccinated against a bacterialinfection caused by a bacterium selected from a Gram-negative bacterium.In one embodiment, the subject is vaccinated against a bacterialinfection caused by a bacterium selected from a Gram-positive bacterium.In one embodiment, the subject is vaccinated against a bacterialinfection caused by the bacterium Neisseria meningitidis, Haemophilusinfluenzae, or Streptococcus pneunemoniae, or a combination of one ormore of Neisseria meningitidis, Haemophilus influenzae, or Streptococcuspneumoniae, and one or more of, but not limited to, Bacillus anthracis,Bordetella pertussis, Clostridium tetani, Corynebacterium diphtheria,Coxiella burnetii, Mycobacterium tuberculosis, Salmonella typhi, Vibriocholerae, Anaplasma phagocytophilum, Ehrlichia ewingii, Ehrlichiachaffeensis, Ehrlichia canis, Neorickettsia sennetsu, Mycobacteriumleprae, Borrelia burgdorferi, Borrelia mayonii, Borrelia afzelii,Borrelia garinii, Mycobacterium bovis, Staphylococcus aureus,Streptococcus pyogenes, Treponema pallidum, Francisella tularensis,Yersinia pestis,

In one embodiment, the subject is vaccinated with one or more vaccinesselected from, but not limited to, typhoid vaccine, live (Vivotif BernaVaccine, PaxVax), typhoid Vi polysaccharide vaccine (Typhim Vi, Sanofi),pneumococcal 23-polyvalent vaccine, PCV13 (Pneumovax 23, Merck),pneumococcal 7-valent vaccine, PCV7 (Prevnar, Pfizer), pneumococcal13-valent vaccine, PCV13 (Prevnar 13, Pfizer), Haemophilus b conjugate(prp-t) vaccine (ActHIB, Sanofi; Hibrix, GSK), Haemophilus b conjugate(hboc) vaccine (HibTITER, Neuron Biotech), Haemophilus b conjugate(prp-omp) vaccine (PedvaxHIB, Merck), Haemophilus b conjugate (prp-t)vaccine/meningococcal conjugate vaccine (MenHibrix, GSK), Haemophilus bconjugate (prp-t) vaccine/meningococcal conjugate vaccine/Hepatitis Bvaccine (Comvax, Merck), meningococcal polysaccharide vaccine (MenomuneA/C/Y/W-135, Sanofi), meningococcal conjugate vaccine/diphtheria CRM197conjugate (Menveo, GSK; Menactra, Sanofi), meningococcal group B vaccine(Bexsero, GSK; Trumenba, Pfizer), anthrax vaccine adsorbed (Biothrax,Emergent Biosolutions), tetanus toxoid (Te Anatoxal Berna, HendricksRegional Health), Bacillus Calmette and Guerin, live, intravesical(TheraCys, Sanofi; Tice BCG, Organon), cholera vaccine, live, oral(Vachora, Sanofi; Dukoral, SBL Vaccines; ShanChol, Shantha Biotec;Micromedex, Truven Health), tetanus toxoids and diphtheria absorbed(Tdap; Decavac, Sanofi; Tenivac, Sanofi; td, Massachusetts BiologicalLabs), diphtheria and tetanus toxois and pertussis (DTap; Daptacel,Sanofi; Infanrix, GSK; Tripedia, Sanofi), diphtheria and tetanus toxoisand pertussis/polio (Kinrix, GSK; Quadracel, Sanofi), diphtheria andtetanus toxois and pertussis tetanus/hepatitis B/polio (Pediarix, GSK),diphtheria and tetanus toxois and pertussis/polio, Haemophilus influenzatype b (Pentacel, Sanofi), and/or diphtheria, and pertussis (Tdap;Boostrix, GSK; Adacel, Sanofi), or a combination thereof.

As described above, a subject receiving a compound of the presentinvention to treat a disorder is prophylactically administered anantibiotic compound in addition to a factor D inhibitor describedherein. In one embodiment, the subject is administered an antibioticcompound for the duration of administration of the active compound toreduce the development of a bacterial infection. Antibiotic compoundsfor concomitant administration with a factor D inhibitor describedherein can be any antibiotic useful in preventing or reducing the effectof a bacterial infection. Antibiotics are well known in the art andinclude, but are not limited to, amikacin (Amikin), gentamicin(Garamycin), kanamycin (Kantrex), neomycin (Neo-Fradin), netilmicin(Netromycin), tobramycin (Nebcin), paromomycin (Humatin), streptomycin,spectinomycin (Trobicin), geldanamycin, herbimycin, rifaximin (Xifaxan),loracarbef (Lorabid), ertapenem (Invanz), doripenem (Doribax),imipenem/cilastatin (Primaxin), meropenem (Merrem), cefadroxil(Duricef), cefazolin (Ancef), cefalotin/cefalothin (Keflin), cephalexin(Keflex), cefaclor (Distaclor), cefamandole (Mandol), cefoxitin(Mefoxin), cefprozil (Cefzil), cefuroxime (Ceftin, Zinnat), cefixime(Cefspan), cefdinir (Omnicef, Cefdiel), cefditoren (Spectracef, Meiact),cefoperazone (Cefobid), cefotaxime (Claforan), cefpodoxime (Vantin)ceftazidime (Fortaz), ceftibuten (Cedax), ceftizoxime (Cefizox),ceftriaxone (Rocephin), cefepime (Maxipime), ceftaroline fosamil(Teflaro), ceftobiprole (Zeftera), teicoplanin (Targocid), vancomycin(Vancocin), telavancin (Vibativ), dalbavancin (Dalvance), oritavancin(Orbactiv), clindamycin (Cleocin), lincomycin (Lincocin), daptomycin(Cubicin), azithromycin (Zithromax, Surnamed, Xithrone), clarithromycin(Biaxin), dirithromycin (Dynabac), erythromycin (Erythocin, Erythroped),roxithromycin, troleandomycin (Tao), telithromycin (Ketek), spiramycin(Rovamycine), aztreonam (Azactam), furazolidone (Furoxone),nitrofurantoin (Macrodantin, Macrobid), linezolid (Zyvox), posizolid,radezolid, torezolid, amoxicillin (Novamox, Amoxil), ampicillin(Principen), azlocillin, carbenicillin (Geocillin), cloxacillin(Tegopen), dicloxacillin (Dynapen), flucloxacillin (Floxapen),mezlocillin (Mezlin), methicillin (Staphcillin), nafcillin (Unipen),oxacillin (Prostaphlin), penicillin G (Pentids), penicillin V (Veetids(Pen-Vee-K), piperacillin (Pipracil), penicillin G (Pfizerpen),temocillin (Negaban), ticarcillin (Ticar), amoxicillin/clavulanate(Augmentin), ampicillin/sulbactam (Unasyn), piperacillin/tazobactam(Zosyn), ticarcillin/clavulanate (Timentin), bacitracin, colistin(Coly-Mycin-S), polymyxin B, ciprofloxacin (Cipro, Ciproxin, Ciprobay),enoxacin (Penetrex), gatifloxacin (Tequin), gemifloxacin (Factive),levofloxacin (Levaquin), lomefloxacin (Maxaquin), moxifloxacin (Avelox),nalidixic acid (NegGram), norfloxacin (Noroxin), ofloxacin (Floxin,Ocuflox), trovafloxacin (Trovan), grepafloxacin (Raxar), sparfloxacin(Zagam), temafloxacin (Omniflox), mafenide (Sulfamylon), sulfacetamide(Sulamyd, Bleph-10), sulfadiazine (Micro-Sulfon), silver sulfadiazine(Silvadene), sulfadimethoxine (Di-Methox, Albon), sulfamethizole(Thiosulfil Forte), sulfamethoxazole (Gantanol), sulfanilamide,sulfasalazine (Azulfidine), sulfisoxazole (Gantrisin),trimethoprim-sulfamethoxazole (Co-trimoxazole) (TMP-SMX) (Bactrim,Septra), sulfonamidochrysoidine (Prontosil), demeclocycline(Declomycin), doxycycline (Vibramycin), minocycline (Minocin),oxytetracycline (Terramycin), tetracycline (Sumycin, Achromycin V,Steclin), clofazimine (Lamprene), dapsone (Avlosulfon), capreomycin(Capastat), cycloserine (Seromycin), ethambutol (Myambutol), ethionamide(Trecator), isoniazid (I.N.H.), pyrazinamide (Aldinamide), rifampicin(Rifadin, Rimactane), rifabutin (Mycobutin), rifapentine (Priftin),streptomycin, arsphenamine (Salvarsan), chloramphenicol (Chloromycetin),fosfomycin (Monurol, Monuril), fusidic acid (Fucidin), metronidazole(Flagyl), mupirocin (Bactroban), platensimycin,quinupristin/dalfopristin (Synercid), thiamphenicol, tigecycline(Tigacyl), tinidazole (Tindamax Fasigyn), trimethoprim (Proloprim,Trimpex), and/or teixobactin, or a combination thereof.

In one embodiment, the subject is administered a prophylactic antibioticselected from cephalosporin, for example, ceftriaxone or cefotaxime,ampicillin-sulbactam, Penicillin G, ampicillin, chloramphenicol,fluoroquinolone, aztreonam, levofloxacin, moxifloxacin, gemifloxacin,vancomycin, clindamycin, cefazolin, azithromycin, meropenem,ceftaroline, tigecycline, clarithromycin, moxifloxacin,trimethoprim/sulfamethoxazole, cefuroxime, axetil, ciprofloxacin,rifampin, minocycline, spiramycin, and cefixime, or a combination of twoor more thereof.

VII. Process of Preparation of Compounds of Formula I, Formula I′ andFormula I″ Abbreviations

-   -   ACN Acetonitrile    -   Ac Acetyl    -   Ac₂O Acetic anhydride    -   AcOEt, EtOAc ethyl acetate    -   AcOH Acetic acid    -   Boc₂O di-tert-butyl dicarbonate    -   Bu Butyl    -   CAN Ceric ammonium nitrate    -   CBz Carboxybenzyl    -   CDI Carbonyldiimidazole    -   CH₃OH, MeOH Methanol    -   CsF Cesium fluoride    -   CuI Cuprous iodide    -   DCM, CH₂Cl₂ Dichloromethane    -   DIEA, DIPEA N,N-diisopropylethylamine    -   DMA N,N-dimethylacetamide    -   DMAP 4-Dimethylaminopyridine    -   DMF N,N-dimethylformamide    -   DMS Dimethyl sulfide    -   DMSO Dimethyl sulfoxide    -   DPPA Diphenyl phosphoryl azide    -   EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide    -   Et Ethyl    -   Et₃N, TEA Triethylamine    -   EtOAc Ethyl acetate    -   EtOH Ethanol    -   HATU        1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide        hexafluorophosphate    -   HCl Hydrochloric acid    -   HOBT Hydroxybenzotriazole    -   iBu, i-Bu, isoBu Isobutyl    -   iPr, i-Pr, isoPr Isopropyl    -   ^(i)Pr₂NEt N,N-diisopropylethylamine    -   K₂CO₃ Potassium carbonate    -   LiOH Lithium hydroxide    -   Me Methyl    -   MeI Methyl iodide    -   Ms Mesyl    -   MsCl Mesyl chloride    -   MTBE Methyl ^(i)butylether    -   Na₂SO₄ Sodium sulfate    -   NaCl Sodium chloride    -   NaH Sodium hydride    -   NaHCO₃ Sodium bicarbonate    -   NBS N-bromo succinimide    -   NCS N-chloro succinimide    -   NEt₃ Trimethylamine    -   NMP N-Methyl-2-pyrrolidone    -   PCC Pyridinium chlorochromate    -   Pd (OAc)₂ Palladium acetate    -   Pd(dppf)Cl₂ [1,1′-Bis(diphenylphosphino)        ferrocene]dichloropalladium(II)    -   Pd(PPh₃)₂Cl₂ Bis(triphenylphosphine)palladium(II) dichloride    -   Pd(PPh₃)₄ Tetrakis(triphenylphosphine)palladium(0)    -   Pd/C Palladium on carbon    -   Pd₂ (dba)₃ Tris(dibenzylideneacetone)dipalladium(0)    -   PMB 4-Methoxybenzyl ether    -   PPh₃ Triphenylphosphine    -   Pr Propyl    -   Py, py Pyridine    -   RT Room temperature    -   TBAF Tetra-n-butylammonium fluoride    -   TBAT Tetrabutylammonium difluorotriphenylsilicate    -   tBu, t-Bu Tert-butyl    -   tBuOK Potassium tert-butoxide    -   TEA Trimethylamine    -   Tf₂O Trifluoromethanesulfonic anhydride    -   TFA Trifluoroacetic acid    -   TIF Tetrahydrofuran    -   TMS Trimethylsilane    -   TMSBr Bromotrimethylsilane    -   TMSCl Chlorotrimethylsilane    -   t_(R) Retention time    -   Troc 2,2,2-Trichlorethoxycarbonyl chloride    -   Zn (CN)₂ Zinc cyanide        General Methods

All nonaqueous reactions were performed under an atmosphere of dry argonor nitrogen gas using anhydrous solvents. The progress of reactions andthe purity of target compounds were determined using one of the twoliquid chromatography (LC) methods listed below. The structure ofstarting materials, intermediates, and final products was confirmed bystandard analytical techniques, including NMR spectroscopy and massspectrometry.

LC Method A

-   -   Instrument: Waters Acquity Ultra Performance LC    -   Column: ACQUITY UPLC BEH C18 2.1×50 mm, 1.7 m    -   Column Temperature: 40° C.    -   Mobile Phase: Solvent A: H₂O+0.05% FA; Solvent B: CH₃CN+0.05% FA    -   Flow Rate: 0.8 mL/min    -   Gradient: 0.24 min @ 15% B, 3.26 min gradient (15-85% B), then        0.5 min @ 85% B.    -   Detection: UV (PDA), ELS, and MS (SQ in EI mode)

LC Method B

-   -   Instrument: Shimadzu LC-2010A HT    -   Column: Athena, C18-WP, 50×4.6 mm, 5 m    -   Column Temperature: 40° C.    -   Mobile Phase: Solvent A: H₂O/CH₃OH/FA=90/10/0.1; Solvent B:        H₂O/CH₃OH/FA=10/90/0.1    -   Flow Rate: 3 mL/min    -   Gradient: 0.4 min @ 30% B, 3.4 min gradient (30-100% B), then        0.8 min @ 100% B    -   Detection: UV (220/254 nm)

LC Method C

-   -   Instrument: Agilent 1100/1200 series LC system with DAD detector    -   Column: Atlantis dC18 (250×4.6) mm, 5 μm    -   Column Temperature: Ambient    -   Mobile Phase A: 0.1% TFA in water, Mobile Phase B: Acetonitrile    -   Flow Rate: 1.0 mL/min    -   Gradient:

Time (min) 0.0 15 20 23 30 % B 10 100 100 10 10 Detection: (210-400 nm)

LC Method D

-   -   Instrument: Shimadzu LC 20AD system with PDA detector    -   Column: Phenomenex Gemini NX C18 (150×4.6) mm, 5 μm    -   Column Temperature: Ambient    -   Mobile Phase A: 10 mM NH₄OAC in water, Mobile Phase B:        Acetonitrile    -   Flow Rate: 1.0 mL/min    -   Gradient:

Time (min) 0.0 15 20 23 30 % B 10 100 100 10 10 Detection: (210-400 nm)

Example 1. General Route of Synthesis

A compound of the present invention can be prepared, for example, from acentral core. In one embodiment, for example, the central core Structure1 is an N-protected aminoacid where X¹ is nitrogen and PG=protectinggroup. In one embodiment, the central core is coupled to an amine togenerate an amide of Structure 2 (wherein L-B includes a C(O)N moiety).Structure 2 can then be deprotected to generate Structure 3. Structure 3is coupled to Structure 4 (A-COOH) to generate a second amide bond,forming a compound within Formula I. The chemistry is illustrated inRoute 1.

Route 1

In an alternative embodiment, central core Structure 5 is reacted with aheterocyclic or heteroaryl compound to generate a compound of Structure6. In one embodiment, Structure 6 is deprotected to generate acarboxylic acid, Structure 7. In one embodiment, Structure 7 is coupledto an amine to generate a compound of Formula I. This chemistry isillustrated in Route 2.

Route 2

In an alternative embodiment, Structure 8 is deprotected to generate anamine which is Structure 9. Structure 9 is then coupled to generate anamide which is Structure 6. Structure 6 is then deprotected to generatea carboxylic acid which is Structure 7. Structure 7 is then coupled toform the amide which falls within Formula I. The chemistry isillustrated in Route 3.

Route 3

In an alternate embodiment, a heteroaryl or aryl moiety, 4-1, is coupledto a central core to generate 4-2. The protected acid, 4-2 is deblockedto form the carboxylic acid, 4-3. The carboxylic acid is then coupled toform an amide (L-B) which is 4-4. The heteroaryl or aryl moiety, A′, canthen be further derivitized to add substituents at the X¹¹, X¹², X¹³ andX¹⁴ positions to generate compounds of Formula I. This chemistry isillustrated in Route 4.

Route 4

In an alternate embodiment, Structure 5-1 is coupled to an acid,Structure 5-2, to generate Structure 5-3. The carboxylic acid, Structure5-3, is deblocked to generate a carboxylic acid which is Structure 5-4.Carboxylic acid Structure 5-4 is coupled to an amine to form the productamide (L-B) which is a compound within Formula I. This chemistry isillustrated in Route 5.

Route 5

Example 2. Examples of Central Synthons

Z^(A) is halogen.

In one embodiment, deuterated L-proline synthons are disclosed.Deuterated synthons include, but are not limited to, for example, thefollowing compounds:

Structure A can be treated with deuterium oxide to generate Structure B.See, Barraclough, P. et al. Tetrahedron Lett. 2005, 46, 4653-4655;Barraclough, P. et al. Org. Biomol. Chem. 2006, 4, 1483-1491 and WO2014/037480 (p. 103). Structure B can be reduced to generate StructureC. See, Barraclough, P. et al. Tetrahedron Lett. 2005, 46, 4653-4655;Barraclough, P. et al. Org. Biomol. Chem. 2006, 4, 1483-1491. StructureC can be treated with Mitsunobu reaction conditions to generateStructure D. Structure B can be treated with DAST to generate StructureE. See, WO 2014/037480. Structure A can be treated with sodiumborodeuteride to generate Structure F. See, Dormoy, J.-R.; Castro, B.Synthesis 1986, 81-82. Compound F can be used to generate Structure K.See, Dormoy, J.-R.; Castro, B. Synthesis 1986, 81-82. Structure B can betreated with a deuterated reducing agent, for example sodiumborodeuteride to generate Structure G. Structure G can be treated withDAST to generate Structure H. Structure F can be used to generateStructure K. See, Dormoy, J.-R.; Castro, B. Synthesis 1986, 81-82.Structure G can be used to generate Structure I. Structure J can beprepared according to Hruby, V. J. et al. J. Am. Chem. Soc. 1979, 101,202-212. Structures A-J can be used to prepare compounds of Formula I.

Example 3. Preparation of Central-L-B Synthons

Routes 1a, 1b and 1c.

In Route 1a, 5-azaspiro[2.4]heptane-4,5-dicarboxylic acid,5-(1,1-dimethylethyl) ester, (4S)-, CAS 209269-08-9, can be prepared asdescribed in Tandon, M. et al. Bioorg. Med. Chem. Lett. 1998, 8,1139-1144. In Step 2, the protected azaspiro[2.4]heptane is coupled toan amine in the presence of an organic solvent, a base and a couplingreagent to generate an amide bond; the L-B moiety. In one embodiment,the amine is (3-chloro-2-fluorophenyl) methanamine. In one embodiment,the organic solvent is DMF. In one embodiment, the base isdiisopropylethylamine. In one embodiment, the coupling reagent is HATU.In Step 3, the protecting group is removed. In one embodiment, thestarting material is reacted with an acid in the presence of an organicsolvent. In one embodiment, the acid is 4N hydrochloric acid. In oneembodiment, the organic solvent is dioxane.

In Route 1b, (4S) 4-oxazolidinecarboxylic acid, hydrochloride is treatedwith an amine protecting reagent. In one embodiment, the amineprotecting reagent is di-tert-butyl dicarbonate. In another embodiment,3,4-oxazolidinedicarboxylic acid, 3-(1,1-dimethylethyl) ester, (4S)-, iscommercially available from JPM2 Pharmaceuticals. In one embodiment thereaction is carried out in an organic solvent in the presence of a base.In one embodiment, the organic solvent is acetonitrile. In oneembodiment, the base is 4-dimentylaminopyridine (DMAP). In Step 2, theprotected 4-oxazolidinecarboxylic acid is coupled to an amine in thepresence of an organic solvent, a base and a coupling reagent togenerate an amide bond; the L-B moiety. In one embodiment, the amine is(3-chloro-2-fluorophenyl) methanamine. In one embodiment, the organicsolvent is DMF. In one embodiment, the base is diisopropylethylamine. Inone embodiment, the coupling reagent is HATU. In Step 3, the protectinggroup is removed. In one embodiment, the starting material is reactedwith an acid in the presence of an organic solvent. In one embodiment,the acid is 4N hydrochloric acid. In one embodiment, the organic solventis dioxane.

In Route 1c,(S)-5-(tert-Butoxycarbonyl)-5-azaspiro[2.4]heptane-6-caboxylic acid, CAS1129634-44-1, is commercially available from Ark Pharm. In Step 2, thecarboxylic acid is coupled to an amine in the presence of an organicsolvent, a base and a coupling reagent to generate an amide bond; theL-B moiety. In one embodiment, the amine is (3-chloro-2-fluorophenyl)methanamine. In one embodiment, the organic solvent is DMF. In oneembodiment, the base is diisopropylethylamine. In one embodiment, thecoupling reagent is HATU. In Step 3, the protecting group is removed. Inone embodiment, the starting material is reacted with an acid in thepresence of an organic solvent. In one embodiment, the acid is 4Nhydrochloric acid. In one embodiment, the organic solvent is dioxane.

Routes 2a, 2b, 2c, and 2d.

In Route 2a, commercially available Boc-L-proline is coupled to an aminein the presence of an organic solvent, a base and a coupling reagent togenerate an amide bond; the L-B moiety. In one embodiment, the amine is(3-chloro-2-fluorophenyl) methanamine. In one embodiment, the organicsolvent is DMF. In one embodiment, the base is diisopropylethylamine. Inone embodiment, the coupling reagent is HATU. In Step 2, the Bocprotecting group is removed. In one embodiment, the starting material isreacted with an acid in the presence of an organic solvent. In oneembodiment, the acid is 4N hydrochloric acid. In one embodiment, theorganic solvent is dioxane.

In Route 2b, commercially available (1R, 3S,5R)-2-[(tert-butoxy)carbonyl]-2-azabicyclo[3.1.0]hexane-3-carboxylicacid, from Enamine, is coupled to an amine in the presence of an organicsolvent, a base and a coupling reagent to generate an amide bond; theL-B moiety. In one embodiment, the amine is (3-chloro-2-fluorophenyl)methanamine. In one embodiment, the organic solvent is DMF. In oneembodiment, the base is diisopropylethylamine. In one embodiment, thecoupling reagent is HATU. In Step 2, the Boc protecting group isremoved. In one embodiment, the starting material is reacted with anacid in the presence of an organic solvent. In one embodiment, the acidis 4N hydrochloric acid. In one embodiment, the organic solvent isdioxane.

In Route 2c, commercially available(2S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid,from Manchester Organics, is coupled to an amine in the presence of anorganic solvent, a base and a coupling reagent to generate an amidebond; the L-B moiety. In one embodiment, the amine is(3-chloro-2-fluorophenyl) methanamine. In one embodiment, the organicsolvent is DMF. In one embodiment, the base is diisopropylethylamine. Inone embodiment, the coupling reagent is HATU. In Step 2, the Bocprotecting group is removed. In one embodiment, the starting material isreacted with an acid in the presence of an organic solvent. In oneembodiment, the acid is 4N hydrochloric acid. In one embodiment, theorganic solvent is dioxane.

In Route 2d, commercially available(S)-1-(tert-butoxycarbonyl)indoline-2-carboxylic acid, from Chem-Impex,is coupled to an amine in the presence of an organic solvent, a base anda coupling reagent to generate an amide bond; the L-B moiety. In oneembodiment, the amine is (3-chloro-2-fluorophenyl) methanamine. In oneembodiment, the organic solvent is DMF. In one embodiment, the base isdiisopropylethylamine. In one embodiment, the coupling reagent is HATU.In Step 2, the Boc protecting group is removed. In one embodiment, thestarting material is reacted with an acid in the presence of an organicsolvent. In one embodiment, the acid is 4N hydrochloric acid. In oneembodiment, the organic solvent is dioxane. This chemistry isillustrated in Scheme 2.

Additional starting materials that can readily be converted toCentral-L-B-Synthons include, but are not limited to:(S)-1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrole-2-carboxylic acid,CAS 90104-21-5, available from Ark Pharm;cyclopent-1-ene-1,2-dicarboxylic acid, CAS 3128-15-2, purchased from ArkPharm; imidazole, 1H-imidazole-1,2-dicarboxylic acid,1-(1,1-dimethylethyl) 2-ethyl ester, CAS 553650-00-3, commerciallyavailable from FCH Group; Boc-L-octahydroindole-2-carboxylic acid can bepurchased from Chem Impex. The compound,

can be prepared according to the procedures disclosed in WO 2004/111041;(S)-Boc-5-oxopyrrolidine-2-carboxylic acid is available from the AldrichChemical Co.;(1S,2S,5R)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]hexane-2-carboxylicacid is available from Ark Pharm; (S)-3-Boc-thiazolidine-2-carboxylicacid is available from Alfa Aesar;(2S,4R)-1-(tert-butoxycarbonyl)-4-chloropyrrolidine-2-carboxylic acid isavailable from Arch Bioscience;(1S,3aR,6aS)-2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylicacid is available from Ark Pharm; 1,2-pyrrolidinedicarboxylic acid,3-[[(phenylmethoxy)carbonyl]amino]-, 1-(1,1-dimethylethyl) ester,(2S,3R) can be prepared as disclosed in WO 2004/007501. The Cbz groupcan be removed and the amino group can be alkylated to generate centralcore compounds of the present invention.

The compound

can be prepared as disclosed by Braun, J. V.; Heymons, Albrecht Berichteder Deutschen Chemischen Gesellschaft [Abteilung] B: Abhandlungen (1930)63B, 502-7.

The compounds (2S,3S,4S)-4-fluoro-3-methoxy-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester and(2R,3R,4R)-3-fluoro-4-methoxy-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester can be prepared as a mixture according to WO2012/093101 to Novartis and the regioisomers can be ultimately separatedonce coupled to generate the central core-L-B synthons. The compound(S)-Boc-5-oxopyrrolidine-2-carboxylic acid is available from the AldrichChemical Co.

Example 4. Synthesis of L-B Moieties

Scheme 4-1: In Step 1 the appropriately substituted dibromo species iscoupled with an appropriate boronic acid as known in the art to form amixture of biaryl and triaryl products from which the desired biarylcompound is isolated. In Step 2 the appropriately substituted biarylspecies is converted to the Grignard reagent with activated magnesium.In Step 3 the appropriately substituted aldehyde is treated with thepreviously prepared Grignard reagent to form an alcohol. In Step 4 theappropriately substituted alcohol is converted to a bromide as known inthe art with carbon tetrabromide and triphenyl phosphine. In Step 5 theappropriately substituted bromide is converted to the Grignard reagentwith activated magnesium.

Example 5. Synthesis of C-L-B Moieties

Scheme 5-1: In Step 1 the appropriately substituted carboxylic acid iscoupled to the appropriately substituted amine as known in the art toform an amide. In Step 2 the appropriately substituted Boc-protectedspecies is deprotected with acid to liberate the free amine. In Step 3the appropriately substituted amine is Cbz-protected as known in the artto form a protected carboxylic acid. In Step 4 the appropriatelysubstituted carboxylic acid can be orthogonally protected as known inthe art to form an ester. In Step 5 the appropriately substituted andprotected alkene is subjected to a carbene to form a bicyclic ring. InStep 6 the appropriately substituted ester is saponified with acid toliberate the carboxylic acid. In Step 7 the appropriately substitutedCbz-protected species is deprotected with hydrogen to liberate the freeamine.

Scheme 5-2: In Step 1 the appropriately substituted sulfide is oxidizedto a sulfoxide as known in the art. Alternatively, in Step 2 theappropriately substituted sulfide is oxidized to a sulfone as known inthe art. In Step 3 the appropriately substituted carboxylic acid iscoupled to the appropriately substituted amine as known in the art toform an amide. In Step 4 the appropriately substituted Boc-protectedspecies is deprotected with acid to liberate the free amine.

Scheme 5-3: In Step 1 the appropriately substituted carboxylic acid isconverted to the acyl chloride as known in the art. In Step 2 theappropriately substituted acyl chloride is converted to the Weinrebamide as known in the art. In Step 3 the appropriately substitutedWeinreb amide is reacted with a Grignard reagent to afford a ketone. Thesynthesis of complex Grignard reagents is described in Example 4. InStep 4 the appropriately substituted carbamate protected amine isdeprotected to liberate the free amine.

Scheme 5-4: In Step 1 the appropriately substituted amide is convertedto a thioamide with Lawesson's reagent. In Step 2 the appropriatelysubstituted Boc-protected amine is deprotected with acid to liberate thefree amine.

Scheme 5-5: In Step 1 the appropriately substituted carboxylic acid isconverted to a Weinreb amide as known in the art. In Step 2 theappropriately substituted Weinreb amide is reduced as known in the artto afford an aldehyde. In Step 3 the appropriately substituted aldehydeis subjected to an amine to form a Schiff base which is subsequentlyquenched in Step 4. In Step 4 the appropriately substituted Schiff baseis subjected to an appropriate nucleophile to form a complex amine. InStep 5 the appropriately substituted Boc-protected species isdeprotected with acid to liberate the free amine.

Scheme 5-6: In Step 1 the appropriately substituted alcohol is subjectedto TMS-Cl as known in the art to afford a silyl ether. In Step 2 theappropriately substituted silyl ether is subjected with sodium cyanideto afford a cyano species. In Step 3 the appropriately substituted cyanospecies is reduced as known in the art to afford an aldehyde. In Step 4the appropriately substituted aldehyde is further reduced with borane toafford an alcohol. In Step 5 the appropriately substituted alcohol isoxidized as known in the art to afford a carboxylic acid. In Step 6 theappropriately substituted carboxylic acid is coupled to theappropriately substituted amine as known in the art to form an amide. InStep 7 the appropriately substituted ester is converted to a methylketone by insitu formation of the Weinreb amide with subsequent attackby the methyl Grignard reagent. In Step 8 the appropriately substitutedmethyl ketone is subjected to bromine to afford a bromide. By choice ofthe appropriate starting material all mixtures of chiral centers may beprepared as described.

Step 1: ((Prop-2-ynyloxy)methyl)benzene (S2)

To a solution of Scheme 5-7 compound S1 (15.5 g, 0.277 mol) in dry DMF(150 mL) was added NaH (12 g, 305 mol) at 0° C. slowly. After stirringat 0° C. for 1 h, BnBr (52 g, 305 mol) was added into the above mixtureat 0° C. The reaction was stirred at room temperature for 16 h. Themixture was quenched with saturated aq. NH₄Cl solution (150 mL) and thenextracted with DCM (300 mL). The organic layer was washed with aq. LiClsolution (150 mL×3), dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by column chromatography on silica gel (eluted withpetroleum ether:ethyl acetate=100:0 to 100:1) to afford the titlecompound (21 g, 53.1% yield) as a colorless oil.

Step 2: ((Propa-1,2-dienyloxy)methyl)benzene (S3)

To a solution of Scheme 5-7 compound S2 (21 g, 0.144 mol) in dry THF(120 ml) was added t-BuOK (4.84 g, 0.0432 mol). The reaction mixture wasstirred at room temperature for 3 h and then concentrated under reducedpressure. Et₂O (200 mL) was added and the resulting mixture wasfiltered. The filtrate was concentrated and purified by columnchromatography on silica gel (eluted with petroleum ether) to afford thetitle compound (13.8 g, 66.3% yield) as a colorless oil.

Step 3: (S)-Ethyl 2-aminopent-4-enoate (S5)

To a solution of Scheme 5-7 compound S4 (5 g, 43.5 mmol) in EtOH (70 mL)was added SOCl₂ (15.52 g, 130.5 mmol) dropwisely at 0° C. The reactionwas stirred at room temperature for 16 h and concentrated. The residuewas triturated with Et₂O (60 mL) and filtered to afford the titlecompound (7 g, yield 89%) as a white powder, which was directly used inthe next reaction without further purification. LC/MS (ESI) m/z: 144(M+H)⁺.

Step 4: (S)-Ethyl 2-(4-nitrophenylsulfonamido)pent-4-enoate (S7)

To a mixture of Scheme 5-7 compound S5 (7 g, 39 mmol) and TEA (9.85 g,97.5 mmol) in DCM (80 mL) was added 4-nitrobenzene-1-sulfonyl chloride(8.63 g, 39 mmol). The reaction mixture was stirred at room temperatureovernight and then quenched with saturated aq. NaHCO₃ solution (100 mL).The resulting mixture was extracted with DCM (50 mL×2). The combinedorganic fractions were washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated. The residue was purified by columnchromatography on silica gel (eluted with petroleum ether:ethylacetate=15:1 to 8:1) to afford the title compound (9.2 g, 71.84% yield)as a yellow oil. LC/MS (ESI) m/z: 327 (M−H)⁺.

Step 5: (S)-Ethyl2-(N-(1-(benzyloxy)allyl)-4-nitrophenylsulfonamido)pent-4-enoate (S8)

To a solution of Scheme 5-7 compound S7 (8.4 g, 25.6 mmol) in MeCN (90mL) was added ((propa-1,2-dienyloxy)methyl)benzene (4.2 g, 28.17 mmol),DPPP (1.06 g, 2.56 mmol), TEA (5.17 g, 51.2 mmol) and Pd(OAc)₂ (576 mg,2.56 mmol). The reaction was degassed and stirred at room temperaturefor 16 h under a N₂ atmosphere. The mixture was concentrated to drynessand the residue was purified by column chromatography on silica gel(eluted with petroleum ether:ethyl acetate=30:1 to 20:1) to afford thetitle compound (8.1 g, 66.67% yield) as a yellow solid.

Step 6: (S)-Ethyl6-(benzyloxy)-1-(4-nitrophenylsulfonyl)-1,2,3,6-tetrahydropyridine-2-carboxylate(S9)

To a solution of Scheme 5-7 compound S8 (8 g, 16.88 mmol) in drydegassed toluene (80 mL) was added Grubbs I catalyst (707 mg, 0.844mmol) under a N₂ atmosphere. The resulting mixture was degassed threetimes and stirred at 80° C. for 20 h under a N₂ atmosphere. Aftercooling to room temperature, the reaction mixture was concentrated andthe residue was purified by column chromatography on silica gel (elutedwith petroleum ether:ethyl acetate=15:1 to 6:1) to afford the titlecompound (6.58 g, 87.31% yield) as a yellow oil. LC/MS (ESI) m/z: 447(M−H)⁺.

Step 7: (S)-Ethyl1-(4-nitrophenylsulfonyl)-1,2,3,6-tetrahydropyridine-2-carboxylate (S10)

To a mixture of Scheme 5-7 compound S9 (6.58 g, 14.72 mmol) andtriethylsilane (5.17 g, 44.16 mmol) in dry DCM (80 mL) was added borontrifluoride etherate (6.27 g, 44.16 mmol) at −75° C. under a N₂atmosphere dropwise. The reaction was stirred at −75° C. for 1 h andthen at room temperature for 3 h. The mixture was quenched withsaturated NaHCO₃ solution (100 mL) and extracted with DCM (60 mL×2). Thecombined organic phases were washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated. The residue was purified by columnchromatography on silica gel (eluted with petroleum ether:ethylacetate=15:1 to 8:1) to afford the title compound (4.5 g, 89.8% yield)as a colorless oil.

Step 8:(S)-1-(4-Nitrophenylsulfonyl)-1,2,3,6-tetrahydropyridine-2-carboxylicacid (S11)

To a mixture of Scheme 5-7 compound S10 (4.5 g, 13.22 mmol) inEtOH/THF/H₂O (40 mL, 1:2:1, V/V) was added LiOH (1.66 g, 39.66 mmol).The reaction mixture was stirred at room temperature for 4 h and thenacidified with aq. HCl solution (1 M) to pH=5. The resulting mixture wasextracted with DCM/MeOH (40 mL×2, 20:1, V/V). The combined organicfractions were washed with brine, dried over anhydrous Na₂SO₄, filteredand concentrated to afford the title compound (3.3 g, 79.9% yield) as ayellow solid which was used directly in the next reaction withoutfurther purification. LC/MS (ESI) m/z: 311 (M−H)⁺.

Step 9:(S)—N-(6-Methylpyridin-2-yl)-1-(4-nitrophenylsulfonyl)-1,2,3,6-tetrahydropyridine-2-carboxamide(S12)

To a solution of Scheme 5-7 compound S11 (1.77 g, 5.76 mmol) indichloroethane (30 mL) was added 6-methylpyridin-2-amine (674 mg, 6.24mmol), EEDQ (2.82 g, 11.34 mmol) and DIPEA (2.22 g, 17 mmol). Thereaction was heated at reflux overnight under a N₂ atmosphere. Aftercooling, the mixture was concentrated and purified by columnchromatography on silica gel (eluted with petroleum ether:ethylacetate=8:1 to 2:1) to afford the title compound (1.4 g, 60.4% yield) asa yellow solid. LC/MS (ESI) m/z: 403 (M+H)⁺.

Step 10:(S)—N-(6-Methylpyridin-2-yl)-1,2,3,6-tetrahydropyridine-2-carboxamide(S13)

To a solution of Scheme 5-7 compound S12 (740 mg, 1.84 mmol) in DMF (8mL) was added K₂CO₃ (762 mg, 5.52 mmol) and 4-methoxybenzenethiol (335mg, 2.4 mmol). The reaction was stirred at room temperature for 24 h.The mixture was diluted with a 10% LiCl solution (40 ml) and extractedwith DCM/MeOH (40 mL×2, 20:1, V/V). The combined organic fractions werewashed with brine, dried over anhydrous Na₂SO₄, filtered and thenconcentrated. The residue was purified by column chromatography onsilica gel (eluted with DCM:MeOH=100:0 to 50:1) to afford Scheme 5-7compound S13 (310 mg, 77.54% yield) as a yellow solid. LC/MS (ESI) m/z:218 (M+H)⁺.

Step 1: Dimethyl 3-(benzyloxy)pentanedioate (S2)

To a solution of Scheme 5-8 compound S1 (24 g, 0.136 mol) and benzyl2,2,2-trichloroacetimidate (513 g, 0.204 mol) incychexane/dichloromethane (600 mL/120 mL) at room temperature was addedtrifluoromethanesulfonic anhydride (cat. 1.2 mL) dropwise. The reactionmixture was stirred at room temperature overnight and filtered. Thefiltrate was washed with sat. NaHCO₃, brine, dried over anhydrousNa₂SO₄, filtered and concentrated. The residue was purified by columnchromatography on silica gel (eluted with petroleum ether:ethylacetate=10:1) to afford the title compound (35 g, 93.3% yield) as ayellow oil.

Step 2: 3-(Benzyloxy)pentane-1,5-diol (S3)

To a solution of Scheme 5-8 compound S2 (35 g, 0.13 mol) in THF(anhydrous, 200 mL) was added lithium aluminium hydride (15 g, 0.39 mol)in portions at 0° C. The mixture was heated to 65° C. for 4 h. Themixture was quenched by aqueous sodium hydroxide solution (15 mL, 15%wt) and water (15 mL+45 mL). The slurry was filtered and the filter cakewas washed with dichloromethane twice, the combined filtrates was driedover sodium sulfate and concentrated to afford the title compound (22 g,79.7% yield) as a yellow oil.

Step 3: ((1,5-Dibromopentan-3-yloxy)methyl)benzene (S4)

To a mixture of Scheme 5-8 compound S3 (22 g, 0.10 mol) and PPh₃ (82.3g, 0.31 mol) in dry dichloromethane (200 mL) was added perbromomethane(86.95 g, 0.26 mol) in dry dichloromethane (50 mL) dropwise at 0° C. Thereaction was stirred at room temperature overnight and concentratedunder reduced pressure to afford a residue, which was purified by silicagel chromatography (petroleum ether:ethyl acetate=80:1) to afford thetitle compound (23 g, 66.7% yield) as a yellow oil.

Step 4:(2S,5R)-2-(3-(Benzyloxy)-5-bromopentyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine(S6)

To a dry-ice/acetone cooled solution of Scheme 5-8 compound S5 (5 g,0.027 mol) in THE (50 ml), was dropwise added n-BuLi (2.5 M, 14.1 mL,0.035 mol) for 30 min. After addition, the reaction was stirred at thistemperature for 30 min, followed by dropwise addition of a solution ofScheme 5-8 compound S4 (13.6 g, 0.04 mol) in THF (20 mL). The reactionmixture was stirred at this temperature for another 30 min and allowedto stir at room temperature for 16 h. The reaction was quenched with aq.NH₄Cl (50 mL) and extracted with ethyl acetate (60 mL×2). The combinedorganic fractions were washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated. The residue was purified by columnchromatography on silica gel (eluted with petroleum ether:ethylacetate=10:1) to afford the title compound (6 g, yield 50.4%) and Scheme5-8 compound S6 (4.8 g) was recovered.

Step 5: (2S)-Methyl 2-amino-5-(benzyloxy)-7-bromoheptanoate HCl salt(S7)

To a mixture of Scheme 5-8 compound S6 (6 g, 0.01 mol) in dioxane (30mL) was added 0.5 M HCl (30 mL, dropwise at 0° C. The reaction wasstirred at room temperature overnight and concentrated under reducedpressure to afford a residue which was co-evaporated with toluene (15mL×2) to afford the product (crude HCl salt, 8 g) as a brown oil. Theresidue was used directly in the next reaction without purification.

Step 6: (2S)-1-tert-Butyl 2-methyl5-(benzyloxy)azepane-1,2-dicarboxylate (S8)

To a mixture of Scheme 5-8 compound S7 (8 g crude) in acetonitrile (80mL) was added DIPEA (9.03 mL, 0.054 mol), followed by sodium iodide(2.05 g, 0.013 mol). The reaction was stirred at 90° C. for 16 h. Thecompound (Boc)₂O (5.97 g, 0.027 mol) was added and the reaction mixturewas stirred at room temperature for 3 h. The resulting mixture wasdiluted with ethyl acetate (100 mL) and washed twice with brine (30mL×2). The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated to afford crude product, which was purified by silica gelchromatography (Petroleum ether:ethyl acetate=20:1) to afford the titlecompound (3.6 g, 72.4% yield) as a colorless oil.

Step 7: tert-Butyl (2S)-1-tert-butyl 2-methyl5-hydroxyazepane-1,2-dicarboxylate (S9)

A solution of Scheme 5-8 compound S8 (1.6 g, 4.40 mmol) and cat. HOAc(1.5 mL) in methanol (35 mL) was degassed three times under a N₂atmosphere, and Pd(OH)₂ (240 mg) was added. The mixture was degassedagain and stirred under a H₂ filled balloon at 50° C. over 12 h. Thereaction was filtered through Celite®, and the filtrate was concentratedto afford the title compound (1.1 g, 91.3% yield) as light yellow oil.

Step 8: (2S)-1-tert-Butyl 2-methyl 5-fluoroazepane-1,2-dicarboxylate(S10)

To a dry-ice/ethanol cooled solution of Scheme 5-8 compound S9 (1.1 g,4.03 mmol) in DCM (20 mL) was added DAST (0.79 mL, 6.04 mmol) dropwise.The reaction mixture was warmed up slowly and stirred at roomtemperature overnight. After quenching with saturated aq.NaHCO₃solution, the mixture was extracted with DCM (20 mL×2). The combinedorganic fractions were washed with water and brine, dried over anhydrousNa₂SO₄, filtered and concentrated to afford crude product which waspurified by silica gel chromatography (petroleum ether:ethylacetate=10:1) to afford the title compound (750 mg, 68.1% yield) as acolorless oil.

Step 9: (2S)-1-(tert-Butoxycarbonyl)-5-fluoroazepane-2-carboxylic acid(S11)

To a mixture of Scheme 5-8 compound S10 (750 mg, 2.72 mmol) in THE (7mL) was added aq. NaOH solution (4 M, 2.7 mL, 10.8 mmol). The reactionwas stirred at 40° C. overnight and concentrated under reduced pressure.The residue was diluted with water (10 mL) and washed with Et₂O (3mL×2). The aqueous layer was acidified with diluted hydrochloric acid (1M) to pH=3. The resulting mixture was extracted with DCM (10 mL×2). Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to afford the titlecompound (700 mg, 98.4% yield) as a white solid

Step 10: (2S)-tert-Butyl5-fluoro-2-(6-methylpyridin-2-ylcarbamoyl)azepane-1-carboxylate (S12)

To a solution of Scheme 5-8 compound S11 (500 mg, 1.91 mmol) and6-methylpyridin-2-amine (248 mg, 2.29 mmol) in DCE (10 ml) was addedDIPEA (0.95 mL, 5.73 mmol) and EEDQ (943.5 mg, 3.82 mmol). The reactionmixture was stirred at 90° C. overnight and concentrated under highvacuum. The residue was purified by silica gel chromatography (petroleumether:ethyl acetate=10:1) to afford the title compound (500 mg, 74.4%yield) as a white solid.

Step 11: (2S)-5-Fluoro-N-(6-methylpyridin-2-yl)azepane-2-carboxamidehydrochloride (S13)

To a mixture of Scheme 5-8 compound S12 (500 mg, 1.42 mmol) in dioxane(2 mL) was added HCl/dioxane (4 M, 5 mL) dropwise at 0° C. The reactionmixture was stirred at room temperature for 2 h and concentrated underreduced pressure to afford Scheme 5-8 compound S13 (550 mg, 100% yield)as a white solid which was used without further purification.

Step 1: (2S,4R)-tert-Butyl4-fluoro-2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (S2)

To a solution of Scheme 5-9 compound S1 (5 g, 21.43 mmol) in DCM (100mL) was added N,O-dimethylhydroxylamine hydrochloride (2.5 g, 25.72mmol), EDCI (6.16 g, 32.14 mmol) and HOBt (2.9 g, 21.43 mmol) followedby TEA (5.4 g, 53.58 mmol) at 0° C. The reaction mixture was stirred atroom temperature for 16 h. The mixture was diluted with DCM and washedwith water and brine, dried over anhydrous Na₂SO₄ and concentrated toafford crude product which was washed with PE/EtOAc (2/1) to afford thetitle compound (5.5 g, 92.88% yield) as a white solid.

Step 2: (2S,4R)-tert-Butyl 4-fluoro-2-formylpyrrolidine-1-carboxylate(S3)

To a solution of Scheme 5-9 compound S2 (5 g, 18.12 mmol) in THE (40 mL)was added LiAlH₄ (1.38 g, 36.23 mmol). The reaction was stirred at 0° C.for 2 h. The reaction was quenched with water (1.38 mL), aq. NaOHsolution (1.38 mL, 15% wt) and water (4 mL) successively. The mixturewas filtered and the filter cake was washed with THF twice. The combinedfiltrates were concentrated to dryness to afford crude product which waspurified on silica gel column chromatography (eluted with petroleumether:ethyl acetate=30:1 to 10:1) to afford the title compound (2.7 g,68.7% yield) as a white solid.

Step 3: (2S,4R)-tert-Butyl4-fluoro-2-((R)-1-hydroxy-2-(6-methylpyridin-2-yl)ethyl)pyrrolidine-1-carboxylate& (2R,4R)-tert-butyl4-fluoro-2-((S)-1-hydroxy-2-(6-methylpyridin-2-yl)ethyl)pyrrolidine-1-carboxylate(S4) and (S4A)

To a stirred solution of 2,6-dimethylpyridine (2.46 g, 23.04 mmol) inTHE (50 mL) was added n-butyllithium (1.6 M in THF, 7.2 mL, 11.52 mmol)dropwise at −70° C. The reaction mixture was stirred at this temperaturefor 1 h and compound 3 (2.5 g, 1.52 mmol) in THE (10 mL) was added at−70° C. for 30 min. The mixture was continued to stir at thistemperature for 1 h and quenched with an aq. NH₄Cl solution. Theresulting mixture was extracted with EtOAc (100 mL). The organic phasewas washed with brine, dried with anhydrous Na₂SO₄ and concentrated. Theresidue was purified on silica gel column chromatography (eluted withpetroleum ether:ethyl acetate=20:1 to 10:1) to afford the title Scheme5-9 compounds S4 (1.2 g, 26.3% yield) and S4A (1.3 g, 28.56% yield) aswhite solids.

Step 4:(R)-1-((2S,4R)-4-Fluoropyrrolidin-2-yl)-2-(6-methylpyridin-2-yl)ethan-1-ol(S5)

To a solution of Scheme 5-9 compound S4 (1.2 g, 3.7 mmol) in dioxane (10mL) was added HCl/dioxane (4 M, 5 mL). The reaction mixture was stirredat room temperature for 1 h. The reaction solution was concentrated toafford Scheme 5-9 compound S5 (1.3 g, 100% yield) as a white solid,which was used without further purification.

Step 5:(S)-1-((2S,4R)-4-Fluoropyrrolidin-2-yl)-2-(6-methylpyridin-2-yl)ethan-1-ol(S5A)

Scheme 5-9 compound S5A was prepared following the procedure in for thesynthesis of scheme 5-9 compound S5. Scheme 5-9 compound S5A was carriedforward without further purification.

Example 6. Synthesis of a Moieties

Scheme 6-1: In Step 1 the appropriately substituted nitro species isreduced with palladium as known in the art to afford an amine. In Step 2the appropriately substituted alkene species is brominated withconcurrent addition of ethanol as known in the art to afford the bromidespecies. In Step 3 the appropriately substituted mixture of tautomers issubjected to the previously prepared bromide species as known in the artto afford the two isomers. The appropriately substituted isomerscorresponding to each tautomer may either be separated or used as amixture in the subsequent reactions with separation at a later step. InStep 4 the appropriately substituted ketal species is deprotected andsubsequently cyclized in the presence of acid as known in the art. InStep 5 the appropriately substituted cyano species is subjected tostrong acid to afford a primary amide. In Step 6 the appropriatelysubstituted heterocycle is subjected to a bromide species of theappropriate linker to afford the appropriately protected species.Various 5-5 fused bicyclic systems can be appropriately prepared byslight modifications of this synthetic protocol, another non-limitingexample is presented in Steps 5 through 12 with the same conditions forformation of a primary amide and installation of linker. In Step 7 theappropriately substituted aryl species is brominated as known in theart. In Step 8 the appropriately substituted ether species isdeprotected with palladium as known in the art to afford an alcohol. InStep 9 the appropriately substituted alcohol is oxidized as known in theart to afford an aldehyde. In Step 10 the appropriately substitutedaldehyde is subjected to hydrazine to first form a Schiff base andsubsequently cyclize to afford a bicyclic system. In Step 11 theappropriately substituted bicyclic system is iodinated as known in theart. In Step 12 the appropriately substituted iodide is subjected tosodium cyanide to afford the cyano species.

Scheme 6-2: Non-limiting examples of amine substituents are provideddemonstrating the robust nature of the synthetic protocol. Amines 1-8are subjected to an appropriately substituted aryl bromide as known inthe art to afford various species.

Scheme 6-3: In Step 1 the appropriately substituted and protectedaniline is converted as known in the art to a sulfonamide. In Step 2 theappropriately substituted alcohol is converted as known in the art to atriflouro sulfonamide. In Step 3 the previously prepared reagents aresubjected to sodium hydride to afford their adduct. In Step 4 theappropriately substituted ketal is subjected to a strong lewis acid toafford deprotection and subsequent cyclization to a biaryl species. InStep 5 the appropriately substituted sulfonamide is deprotected in thepresence of base to afford a free amine. In an alternative embodimentthis synthetic protocol can be applied to other aniline isomers toafford substituents on alternative positions.

Scheme 6-4: In Step 1 the appropriately substituted indole is acylatedas known in the art. In Step 2 the appropriately substituted heterocycleis subjected to a bromide species of the appropriate linker to affordthe appropriately protected species. In Step 3 the appropriatelysubstituted aryl bromide is subjected to a sulfonamide as known in theart to afford an aryl sulfonamide. In Step 4 the appropriatelysubstituted benzyl alcohol is deprotected in the presence of hydrogengas and palladium to afford a free alcohol. In Step 5 the appropriatelysubstituted phenol is subjected to a sulfonic anhydride to afford aleaving group. In Step 6 the appropriately substituted aryl species isconverted to a boronic acid as known in the art. In Step 7 theappropriately substituted boronic acid is subjected to copper bromide toafford an aryl bromide species. In an alternative embodiment thissynthetic protocol can simply be applied to other indole isomers toafford substituents on alternative positions.

Scheme 6-5: Non-limiting examples of amine substituents are provideddemonstrating the robust nature of the synthetic protocol. Amines 1-8are subjected to an appropriately substituted aryl bromide as known inthe art to afford various species.

Example 7. Synthesis of L3-A Moieties

Scheme 7-1: In Step 1 the appropriately substituted aryl compound issubjected to a bromide to afford a sulfonic acid substituted species. InStep 2 the appropriately substituted sulfonic acid species ischlorinated as known in the art.

Scheme 7-2: In Step 1 the appropriately substituted aryl compound issubjected to a chloride to afford a phosphonic acid substituted species.In Step 2 the appropriately substituted phosphonic acid species ischlorinated as known in the art.

Example 8. Coupling of L3-A to C-L-B

Scheme 8-1: In Step 1 the appropriately substituted amine is subjectedto a sulfonyl chloride which can be prepared as described in Scheme 7-1to afford a compound of Formula I.

Scheme 8-2: In Step 1 the appropriately substituted amine is subjectedto a phosphonic dichloride which can be prepared as described in Scheme7-2 followed by a subsequent quench with water to afford a compound ofFormula I.

Scheme 8-3: In Step 1 the appropriately substituted oxetane is subjectedto conditions known in the art to form an amino/cyano substitutedspecies. In Step 2 the appropriately substituted cyano species isreduced as known in the art to afford an aldehyde. In Step 3 theappropriately substituted aldehyde is reduced with borane to afford analcohol. In Step 4 the appropriately substituted alcohol is converted toa bromide as known in the art. In Step 5 the appropriately substitutedbromide is subjected to a heteroaryl species as known in the art toafford a compound of Formula I.

Scheme 8-4: In Step 1 the appropriately substituted bromide is subjectedto a heteroaryl species to afford a compound of Formula I.

Scheme 8-5: In Step 1 the appropriately substituted carboxylic acid iscoupled to the appropriately substituted amine as known in the art toform a compound of Formula I.

Scheme 8-6: To a mixture of Scheme 8-6 compound S1,2-(3-carbamoyl-5-(3,3-difluoropiperidine-1-carboxamido)-1H-indol-1-yl)aceticacid, and the appropriate amine in DMF (1 mL) at 0° C. was added DIPEAfollowed by HATU. After addition, the reaction was stirred at roomtemperature for 16 hrs. The mixture was diluted with EtOAc and washedwith water and 10% aq. LiCl solution, dried over anhydrous Na₂SO₄,filtered and concentrated to afford crude product, which was purified bypreparative HPLC to afford the desired compound.

Scheme 8-6 compound S2: LC/MS (ESI) m/z: 580 [M+1]⁺.

Scheme 8-6 compound S3: ¹H NMR (400 MHz, DMSO-d₆) δ 8.57 (s, 1H), 8.11(s, 1H), 7.89 (s, 1H), 7.69-7.51 (m, 1H), 7.27 (dd, J=14.5, 5.4 Hz, 2H),7.09 (ddd, J=31.4, 19.6, 8.9 Hz, 3H), 5.84-5.48 (m, 1H), 5.39 (d, J=17.0Hz, 1H), 5.25-5.03 (m, 2H), 4.47-4.32 (m, 1H), 4.30-4.00 (m, 2H), 3.79(t, J=12.2 Hz, 3H), 3.55-3.47 (m, 2H), 2.98-2.58 (m, 3H), 2.45 (d, J=5.7Hz, 2H), 2.42 (s, 2H), 2.37-2.16 (m, 2H), 2.11-1.98 (m, 2H), 1.71 (d,J=11.5 Hz, 2H). LC/MS (ESI) m/z: 587 [M+1]⁺.

Scheme 8-6 compound S4: ¹H NMR (400 MHz, DMSO-d₆) δ 8.60 (d, J=5.5 Hz,1H), 8.32 (t, J=7.8 Hz, 1H), 8.10 (t, J=7.2 Hz, 1H), 7.93 (d, J=15.7 Hz,1H), 7.70 (d, J=7.8 Hz, 2H), 7.38-7.25 (m, 2H), 5.53-5.21 (m, 2H), 5.03(d, J=17.3 Hz, 1H), 4.64-4.33 (m, 2H), 4.18 (s, 2H), 3.80 (d, J=12.1 Hz,3H), 3.51 (d, J=5.0 Hz, 2H), 3.13 (d, J=10.3 Hz, 1H), 2.93 (dd, J=14.0,9.9 Hz, 1H), 2.71 (s, 2H), 2.43-2.12 (m, 2H), 2.12-1.99 (m, 2H), 1.70(s, 2H). LC/MS (ESI) m/z: 587 [M+1]⁺.

Scheme 8-6 compound S5: ¹H NMR (400 MHz, DMSO-d₆) δ 10.42 (s, 1H), 8.58(s, 1H), 8.17-8.10 (m, 1H), 7.90 (s, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.63(t, J=7.9 Hz, 1H), 7.33-7.22 (m, 2H), 6.94 (d, J=7.5 Hz, 1H), 5.43 (d,J=17.3 Hz, 1H), 5.19 (d, J=17.2 Hz, 1H), 4.81 (s, 2H), 3.95 (d, J=15.9Hz, 1H), 3.79 (t, J=12.1 Hz, 2H), 3.54-3.48 (m, 2H), 2.39 (d, J=17.3 Hz,3H), 2.10 (ddd, J=35.2, 24.3, 20.9 Hz, 4H), 1.91-1.64 (m, 4H), 1.24 (s,1H). LC/MS (ESI) m/z: 614 [M+1]⁺.

Step 1: tert-Butyl2-(3-carbamoyl-5-(pyridazin-3-ylamino)-1H-indol-1-yl)acetate (S2)

A solution of Scheme 8-7 compound S1 (100 mg, 1.25 mmol) in EtOH (10 mL)was degassed under a N₂ atmosphere three times and Pd/C (20 mg, 10% wt)was added. The mixture was degassed again and stirred under a H₂ filledballoon at room temperature for 2 hours. After filtration, the filtratewas concentrated to dryness. The obtained residue was purified by silicagel chromatography (dichloromethane:methanol=100:1 to 80:1) to affordthe title compound (35 mg, 38.2% yield) as alight yellow solid. LC-MS(ESI) found: 368 [M+1]⁺.

Step 2: 2-(3-Carbamoyl-5-(pyridazin-3-ylamino)-1H-indol-1-yl)acetic acid(S3)

To a solution of Scheme 8-7 compound S2 (35 mg, 0.095 mmol) in DCM (1mL) was added TFA (0.2 mL). After addition, the reaction was stirred atroom temperature for 3 h. The resulting mixture was concentrated todryness to afford the title compound (33 mg, 100% yield) as brown solid.LC-MS (ESI) found: 312 [M+1]⁺.

Step 3:(S)-1-(2-(6-(6-Methylpyridin-2-ylcarbamoyl)-5,6-dihydropyridin-1(2H)-yl)-2-oxoethyl)-5-(pyridazin-3-ylamino)-1H-indole-3-carboxamide(1)

To a mixture of Scheme 8-7 compound S3 (33 mg, 0.095 mmol) and Scheme8-7 S4 (20.6 mg, 0.095 mmol) in DMF was added DIPEA (49 mg, 0.38 mol)and HATU (72.2 mg, 0.19 mol) at 0° C. and the resulting mixture wasstirred at room temperature for 16 hours. The mixture was diluted withEtOAc and washed with water and 10% aq. LiCl solution, dried overanhydrous Na₂SO₄, filtered and concentrated to afford crude product,which was purified by preparative HPLC to afford the title compound 1(5.1 mg, 10.5% yield) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.47 (s, 1H), 9.12 (s, 1H), 8.57 (d, J=4.4Hz, 1H), 8.31 (s, 1H), 7.91 (s, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.70-7.54(m, 2H), 7.36 (dd, J=13.8, 6.5 Hz, 2H), 7.00 (dd, J=38.6, 8.2 Hz, 2H),5.84 (s, 2H), 5.51-5.21 (m, 2H), 4.38 (s, 1H), 2.67 (s, 1H), 2.53 (s,1H), 2.41 (d, J=16.2 Hz, 3H), 1.43-1.33 (m, 1H). LC-MS (ESI) found: 511[M+1]⁺.

Example 9. Synthesis of Amino Compounds of Formula I, Formula I′ andFormula I″ Synthesis of(2S,4R)-1-(2-(3-acetyl-5-((6-(2-methoxyethoxy)pyridin-3-yl)amino)-1H-indol-1-yl)acetyl)-N-(3-(7-chloro-2-oxoindolin-6-yl)-2-fluorophenyl)-4-fluoropyrrolidine-2-carboxamide

Scheme 9-1

Step 1: 6-Bromo-7-chloroindolin-2-one (S2)

To a solution of Scheme 9-1 compound 1 (1 equiv) in acetonitrile (10vol) at 0° C. was added NBS (1.1 equiv). The reaction mixture wasstirred at room temperature for 3 h and then quenched with water. Theresulting mixture was extracted with ethyl acetate. The organic layerwas separated, dried over anhydrous Na₂SO₄, filtered and thenconcentrated. The residue was purified by column chromatography onsilica gel to afford Scheme 9-1 compound 2.

Scheme 9-2

Step 1: tert-Butyl2-(3-acetyl-5-((6-(2-methoxyethoxy)pyridin-3-yl)amino)-1H-indol-1-yl)acetate(S2)

To a mixture of Scheme 9-2 compound 3 (1 equiv) and6-(2-methoxyethoxy)pyridin-3-amine (1 equiv) in DMF (10 vol) was addedxanthphos (0.15 equiv), cesium carbonate (1.4 equiv) and Pd₂(dba)₃ (0.1equiv). After degassing with nitrogen, the resulting mixture was stirredat 100° C. for 24 h and then cooled to room temperature. Water was addedto the reaction mixture and the resulting mixture was extracted withethyl acetate. The organic layer was separated, dried over anhydrousNa₂SO₄, filtered and then concentrated. The residue was purified bycolumn chromatography on silica gel to afford Scheme 9-2 compound 4.

Step 2:tert-Butyl-2-(3-acetyl-5-((6-(2-methoxyethoxy)pyridin-3-yl)((2,2,2-trichloroethoxy)carbonyl)amino)-1H-indol-1-yl)acetate(S3)

To a solution of Scheme 9-2 compound 4 (1 equiv) and potassium carbonate(2 equiv) in DCM (10 vol) at 0° C. was added Troc-Cl (1.1 equiv). Thereaction mixture was stirred at room temperature for 12 h and thenquenched with water. The resulting mixture was extracted with ethylacetate. The organic layer was separated, dried over anhydrous Na₂SO₄,filtered and then concentrated. The residue was purified by columnchromatography on silica gel to afford Scheme 9-2 compound 5.

Step 3:2-(3-Acetyl-5-((6-(2-methoxyethoxy)pyridin-3-yl)((2,2,2-trichloroethoxy)carbonyl)amino)-1H-indol-1-yl)aceticacid (S4)

To a solution of Scheme 9-2 compound 5 (1 equiv) in DCM (10 vol) at 0°C. was added TFA (5 vol). The reaction mixture was stirred at 50° C. for3 h and then concentrated. The residue was re-crystallized from MTBE toafford Scheme 9-2 compound 6.

Scheme 9-3

Step 1: tert-Butyl(2S,4R)-2-((3-bromo-2-fluorophenyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate(S2)

To a solution of 3-bromo-2-fluoroaniline (1.2 equiv) and Scheme 9-3compound S1 (1 equiv) in DMF (10 vol) at 0° C. was added DIPEA (2 equiv)and HATU (1.2 equiv). The reaction mixture was stirred at roomtemperature for 16 h and then quenched with water. The resultant solidwas filtered, washed with MTBE to afford Scheme 9-3 compound S2.

Step 2: tert-Butyl(2S,4R)-4-fluoro-2-((2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamoyl)pyrrolidine-1-carboxylate(S3)

To a mixture of Scheme 9-3 compound S2 (1 equiv) andBis(pinacolato)diboron(1.1 equiv) in DMF (10 vol) was added PdCl₂(PPh₃)₂(0.1 equiv) and potassium acetate (2 equiv). After degassing withnitrogen, the resulting mixture was stirred at 100° C. for 24 h and thencooled to room temperature. Water was added to the reaction mixture andthe resulting mixture was extracted with ethyl acetate. The organiclayer was separated, dried over anhydrous Na₂SO₄, filtered and thenconcentrated. The residue was purified by column chromatography onsilica gel to afford Scheme 9-3 compound S3.

Step 3: tert-Butyl(2S,4R)-2-((3-(7-chloro-2-oxoindolin-6-yl)-2-fluorophenyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate(S4)

To a mixture of Scheme 9-3 compound S3 (1.5 equiv) and Scheme 9-1compound S2 (1 equiv) in DMF/water (10:1) was added cesium carbonate(1.4 equiv) and Pd(PPh₃)₄. After degassing with nitrogen, the resultingmixture was stirred at 100° C. for 12 h and then cooled to roomtemperature. Water was added to the reaction mixture and the resultingmixture was extracted with ethyl acetate. The organic layer wasseparated, dried over anhydrous Na₂SO₄, filtered and then concentrated.The residue was purified by column chromatography on silica gel toafford Scheme 9-3 compound S4.

Step 4:(2S,4R)—N-(3-(7-Chloro-2-oxoindolin-6-yl)-2-fluorophenyl)-4-fluoropyrrolidine-2-carboxamide(S5)

To a solution of Scheme 9-3 compound S4 (1 equiv) in DCM (10 vol) at 0°C. was added TFA (5 vol). The reaction mixture was stirred at 50° C. for3 h and then concentrated. The residue was re-crystallized from MTBE toafford Scheme 9-3 compound S5.

Step 5:(2S,4R)-1-(2-(3-Acetyl-5-((6-(2-methoxyethoxy)pyridin-3-yl)amino)-1H-indol-1-yl)acetyl)-N-(3-(7-chloro-2-oxoindolin-6-yl)-2-fluorophenyl)-4-fluoropyrrolidine-2-carboxamide(S6)

To a solution of Scheme 9-3 compound S5 (1.2 equiv) and Scheme 9-2compound S4 (1 equiv) in DMF (10 vol) at 0° C. was added DIPEA (2 equiv)and HATU (1.2 equiv). The reaction mixture was stirred at roomtemperature for 16 h and then quenched with water. The resulting mixturewas extracted with ethyl acetate. The organic layer was separated, driedover anhydrous Na₂SO₄, filtered and then concentrated. The residue waspurified by column chromatography on silica gel to afford Scheme 9-3compound S6.

Example 10. Synthesis of Amino Compounds of Formula I′

Scheme 10-1: In Step 1 the appropriately substituted bromide wassubjected to a phthalimide to afford a protected alkene species. In Step2 the appropriately substituted phthalimide-protected amine wassubjected to hydrazine as known in the art to afford a free amine. InStep 3 the two appropriately substituted species previously preparedreact as known in the art to afford a terminal alkene species. In Step 4the appropriately substituted ester was treated with TFA to afford acarboxylic acid. In Step 5 the appropriately substituted carboxylic acidwas converted to an amide as known in the art. In Step 6 the di-alkenespecies was cyclized as known in the art to form a macrocyclic species.In Step 7 the appropriately substituted macrocyclic-alkene species wasreduced with hydrogen to afford a macrocyclic-alkyl species.

Example 11. Non-Limiting Examples of Amino Compounds of Formula I

In the illustrative compounds in FIG. 16 , and elsewhere herein, R³² wasdepicted as Z₃₂, which are intended to be the same moieties.

Example 12. Human Factor D Assay

Human Factor D (purified from human serum, Complement Technology, Inc.)at 80 nM final concentration was incubated with test compound at variousconcentrations for 5 minutes at room temperature in 50 mM Tris, 1M NaCl,pH 7.5. A synthetic substrate Z-L-Lys-SBzl and DTNB (Ellman's reagent)are added to final concentrations of 100 μM each. Absorbance at 405 nm(A₄₀₅) was recorded at 30 second intervals for 30 minutes using amicroplate spectrophotometer. IC₅₀ values are calculated by nonlinearregression of complement Factor D reaction rates as a function of testcompound concentration.

Example 13. Hemolysis Assay

The hemolysis assay was previously described by G. Ruiz-Gomez, et al.,J. Med. Chem. (2009) 52: 6042-6052. Prior to the assay, the optimumconcentration of Normal Human Serum (NHS) needed to achieve 100% lysisof rabbit erythrocytes (RE) was determined by titration. In the assay,NHS (Complement Technology) was diluted in GVB⁰ Buffer (0.1% gelatin, 5mM Veronal, 145 mM NaCl, 0.025% NaN₃, pH 7.3, Complement Technology)plus 10 mM Mg-EGTA and incubated with test compound at variousconcentrations for 15 minutes at 37° C. RE (Complement Technology)freshly suspended in GVB⁰ plus 10 mM Mg-EGTA are added to a finalconcentration of 1×10⁸ cells/mL and reactions are incubated for 30minutes at 37° C. Positive control reactions (100% lysis) consist ofGVB⁰ plus 10 mM Mg-EGTA with NHS and RE but without test compound;negative control reactions (0% lysis) consist of GVB⁰ plus 10 mM Mg-EGTAwith RE only. Samples are centrifuged at 2000 g for 3 minutes andsupernatants collected. Absorbance at 405 nm (A₄₀₅) was recorded using amicroplate spectrophotometer. IC₅₀ values are calculated by nonlinearregression from the percentage of hemolysis as a function of testcompound concentration.

Example 14. Non-Limiting Examples of Compounds of Formula I

Table 3 shows illustrative compounds of Formula I with characterizingdata. The assay of Example 12 was used to determine the IC₅₀'s of thecompounds. Other standard Factor D inhibition assays are also available.Three ***s are used to denote compounds with an IC₅₀ less than 1micromolar; two **s indicate compound with an IC₅₀ between 1 micromolarand 10 micromolar, and one * denotes compounds with an IC₅₀ greater than10 micromolar.

TABLE 3 Non-limiting Examples of Compounds of Formula I RT min Cmp(Method MS No. Structure Name IC₅₀ A or B) (M + 1) 1

(S)-1-(2-(6-((6- methylpyridin-2- yl)carbamoyl)-5,6- dihydropyridin-1(2H)-yl)-2- oxoethyl)-5- (pyridazin-3- ylamino)-1H- indole-3-carboxamide * 3.53 (B) 511

This specification has been described with reference to embodiments ofthe invention. However, one of ordinary skill in the art appreciatesthat various modifications and changes can be made without departingfrom the scope of the invention as set forth in the claims below.Accordingly, the specification is to be regarded in an illustrativerather than a restrictive sense, and all such modifications are intendedto be included within the scope of invention.

We claim:
 1. A method for the treatment of a disorder mediated bycomplement factor D, comprising administering to a host in need thereofan effective amount of a compound of formula

or a pharmaceutically acceptable salt thereof, wherein A is A1; B is B1or B4; L is L1; L3 is L4 or L5; A1 is

B1 is selected from the group consisting of a monocyclic or bicycliccarbocyclic; a monocyclic or bicyclic carbocyclic-oxy group; amonocyclic, bicyclic, or tricyclic heterocyclic group having 1, 2, 3, or4 heteroatoms independently selected from N, O, and S and from 4 to 7ring atoms per ring; —(C₀-C₄alkyl)(aryl); —(C₀-C₄alkyl)(heteroaryl); and—(C₀-C₄alkyl)(biphenyl), each of which B1 is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of R³³ and R³⁴, and 0 or 1 substituents selectedfrom the group consisting of R³⁵ and R³⁶; B4 is selected from the groupconsisting of: (i) a 4-membered carbocyclic fused to a 5- or 6-memberedheteroaryl having 1, 2, or 3 heteroatoms independently selected from N,O, and S; (ii) a 4-membered carbocyclic fused to a 6-membered aryl ring;and (iii) (cycloalkyl)-(aryl), (cycloalkyl)-(heteroaryl),(cycloalkyl)-(heterocycle), (alkyl)-alkenyl, or cycloalkyl-alkenyl;wherein B4 can be substituted 1, 2, 3 or 4 times with the substituentsindependently selected from the group consisting of R³³, R³⁴, R³⁵, R³⁶and R⁴⁸; L1 is a bond or is selected from the group consisting offormulas

L4 is —C(O)—; L5 is —C(S)—, —P(O)OH—, —S(O)—, —S(O)₂— or —C(R⁵²)₂—; X¹¹is N or CR¹¹; X¹² is CR¹²; X¹³ is CR¹³; X¹⁴ is N or CR¹⁴; R⁶ is selectedfrom the group consisting of hydrogen, -JCHO, -JC(O)NH₂,-JC₂-C₆alkanoyl, -JC(O)NH(CH₃), -J-COOH, -JP(O)(OR⁹)₂, -JOC(O)R⁹,-JC(O)OR⁹, -JC(O)N(CH₂CH₂R⁹)(R¹⁰), -JNR⁹C(O)R¹⁰, -JSO₂NH₂, -JS(O)NH₂,-JC(CH₃)₂F, -JCH(CF₃)NH₂, -JC(O)C₀-C₂alkyl(C₃-C₇cycloalkyl),-JNR⁹(C₂-C₆alkanoyl), -JNR⁹C(O)NR⁹R¹⁰, -JSO₂(C₁-C₆alkyl),-JSO₂(C₁-C₆haloalkyl), -JSO₂NR⁷R⁷, -JSO═NH(C₁-C₆alkyl), -J-nitro,-J-halogen, -J-hydroxyl, -J-phenyl, a 5- to 6-membered heteroaryl,-J-cyano, -J-cyanoimino, -J-amino, -J-imino, —C₁-C₆alkyl,—C₀-C₄alkyl(C₃-C₇heterocycloalkyl), —C₀-C₄alkyl(C₃-C₇cycloalkyl),

each R⁶ other than hydrogen, nitro, halogen, cyano, cyanoimino, or —CHOis unsubstituted or substituted with one or more substituents selectedfrom the group consisting of amino, imino, halogen, hydroxyl, cyano,cyanoimino, C₁-C₂alkyl, C₁-C₂alkoxy, —C₀-C₂alkyl(mono- anddi-C₁-C₄alkylamino), C₁-C₂haloalkyl, and C₁-C₂haloalkoxy; R⁷ ishydrogen, C₁-C₆alkyl, or —C₀-C₄alkyl(C₃-C₇cycloalkyl); R⁸ and R^(8′) areindependently selected from the group consisting of hydrogen, halogen,hydroxyl, C₁-C₆alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₆alkoxy, and(C₁-C₄alkylamino)C₀-C₂alkyl; or R⁸ and R^(8′) are taken together to forman oxo group; or R⁸ and R^(8′) can be taken together with the carbonthat they are bonded to form a 3-membered carbocyclic ring; R⁹ and R¹⁰are independently selected at each occurrence from the group consistingof hydrogen, C₁-C₆alkyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl,—C₀-C₄alkyl(C₃-C₇cycloalkyl), and —O—C₀-C₄alkyl(C₃-C₇cycloalkyl); R¹¹and R¹⁴ are independently selected at each occurrence from the groupconsisting of hydrogen, halogen, hydroxyl, nitro, cyano, —O(PO)(OR⁹)₂,—(PO)(OR⁹)₂, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₂-C₆alkenyl(aryl),C₂-C₆alkenyl(cycloalkyl), C₂-C₆alkenyl(heterocycle),C₂-C₆alkenyl(heteroaryl), C₂-C₆alkynyl, C₂-C₆alkynyl(aryl),C₂-C₆alkynyl(cycloalkyl), C₂-C₆alkynyl(heterocycle),C₂-C₆alkynyl(heteroaryl), C₂-C₆alkanoyl, C₁-C₆alkoxy, C₁-C₆thioalkyl,—C₀-C₄alkyl(mono- and di-C₁-C₆alkylamino), —C₀-C₄alkyl(C₃-C₇cycloalkyl),—C₀-C₄alkoxy(C₃-C₇cycloalkyl), C₁-C₂haloalkyl, and C₁-C₂haloalkoxy; oneof R¹² and R¹³ is chosen from R³¹ and the other of R¹² and R¹³ is chosenfrom R³² or both R¹² and R¹³ are each independently selected from a R³²;R¹⁷ is hydrogen, C₁-C₆alkyl, or —C₀-C₂alkyl(C₃-C₇cycloalkyl); R¹⁸ andR^(18′) are independently selected from the group consisting ofhydrogen, halogen, hydroxymethyl, and methyl; m is 0, 1, 2, or 3; R²¹and R²² are independently selected at each occurrence from the groupconsisting of hydrogen, hydroxyl, cyano, amino, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆alkoxy, (C₃-C₇cycloalkyl)C₀-C₄alkyl,(phenyl)C₀-C₄alkyl, —C₁-C₄alkylOC(O)OC₁-C₆alkyl,—C₁-C₄alkylOC(O)C₁-C₆alkyl, —C₁-C₄alkylC(O)OC₁-C₆alkyl, (4- to7-membered heterocycloalkyl)C₀-C₄alkyl having 1, 2, or 3 heteroatomsindependently selected from N, O, and S, and (5- or 6-memberedunsaturated or aromatic heterocycle)C₀-C₄alkyl having 1, 2, or 3heteroatoms independently selected from N, O, and S; R²³ isindependently selected at each occurrence from the group consisting ofC₁-C₆alkyl, C₁-C₆haloalkyl, (aryl)C₀-C₄alkyl,(C₃-C₇cycloalkyl)C₀-C₄alkyl, (phenyl)C₀-C₄alkyl, (4- to 7-memberedheterocycloalkyl)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S, and (5- or 6-membered unsaturated or aromaticheterocycle)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S; R³¹ is selected from the group consisting ofhydrogen, halogen, hydroxyl, nitro, cyano, amino, —COOH, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, C₁-C₆alkyl, —C₀-C₄alkyl(C₃-C₇cycloalkyl), C₂-C₆alkenyl,C₂-C₆alkanoyl, C₁-C₆alkoxy, C₂-C₆alkenyloxy, —C(O)OR⁹, C₁-C₆thioalkyl,—C₀-C₄alkylNR⁹R¹⁰, —C(O)NR⁹R¹⁰, —SO₂R⁹, —SO₂NR⁹R¹⁰, —OC(O)R⁹, and—C(NR⁹)NR⁹R¹⁰, each of which R³¹ other than hydrogen, halogen, hydroxyl,nitro, cyano, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, hydroxyl, nitro, cyano, amino, —COOH,—CONH₂, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy, and each of which R³¹ isalso optionally substituted with one substituent selected from the groupconsisting of phenyl and 4- to 7-membered heterocycle containing 1, 2,or 3 heteroatoms independently selected from N, O, and S; which phenylor 4- to 7-membered heterocycle is unsubstituted or substituted with oneor more substituents independently selected from the group consisting ofhalogen, hydroxyl, nitro, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkanoyl, C₁-C₆alkoxy, (mono- and di-C₁-C₆alkylamino)C₀-C₄alkyl,C₁-C₆alkylester, —C₀-C₄alkyl(C₃-C₇cycloalkyl), C₁-C₂haloalkyl, andC₁-C₂haloalkoxy; R³² is selected from the group consisting of NR⁷²R⁷³,NR⁹SOR⁷³, and N(SO₂R⁹)CH₂C(O)R⁷⁴; R⁷² is selected at each occurrencefrom the group consisting of aryl, heteroaryl, heterocycle, alkynyl,hydroxyl, C₁-C₆alkoxy, (C₃-C₇cycloalkyl)C₀-C₄alkyl, (aryl)C₀-C₄alkyl,(heterocycle)C₀-C₄alkyl, (heteroaryl)C₀-C₄alkyl,—C₁-C₄alkylOC(O)OC₁-C₆alkyl, —C₁-C₄alkylOC(O)C₁-C₆alkyl,—C₁-C₄alkylC(O)OC₁-C₆alkyl, —S(O)(O)(alkyl), —S(O)(alkyl),—S(O)(O)(heteroalkyl), —S(O)(heteroalkyl), —S(O)(O)(aryl), —S(O)(aryl),—S(O)(O)(heteroaryl), —S(O)(heteroaryl), (4- to 7-memberedheterocycloalkyl)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S, and (5- or 6-membered saturated or partiallyunsaturated heterocycle)C₀-C₄alkyl having 1, 2, or 3 heteroatomsindependently selected from N, O, and S; R⁷³ is selected at eachoccurrence from the group consisting of hydrogen, hydroxyl, cyano,amino, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,(C₃-C₇cycloalkyl)C₀-C₄alkyl, (phenyl)C₀-C₄alkyl,—C₁-C₄alkylOC(O)OC₁-C₆alkyl, —C₁-C₄alkylOC(O)C₁-C₆alkyl,—C₁-C₄alkylC(O)OC₁-C₆alkyl, (4- to 7-memberedheterocycloalkyl)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S, and (5- or 6-membered unsaturated or aromaticheterocycle)C₀-C₄alkyl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S; R⁷⁴ is a proline amide; R³³ is independentlyselected from the group consisting of halogen, hydroxyl, —COOH, cyano,C₁-C₆alkyl, C₂-C₆alkanoyl, C₁-C₆alkoxy, —C₀-C₄alkylNR⁹R¹⁰, —SO₂R⁹,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy; R³⁴ is independently selected fromthe group consisting of nitro, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆thioalkyl, -JC₃-C₇cycloalkyl, —B(OH)₂, -JC(O)NR⁹R²³, -JOSO₂R²¹,—C(O)(CH₂)₁₋₄S(O)R²¹, —O(CH₂)₁₋₄S(O)NR²¹R²², -JOP(O)(OR²¹)(OR²²),-JP(O)(OR²¹)(OR²²), -JOP(O)(OR²¹)R²², -JP(O)(OR²¹)R²², -JOP(O)R²¹R²²,-JP(O)R²¹R²², -JSP(O)(OR²¹)(OR²²), -JSP(O)(OR²¹)(OR²²),-JSP(O)(R²¹)(R²²), -JNR⁹P(O)(NHR²¹)(NHR²²), -JNR⁹P(O)(OR²¹)(NHR²²),-JNR⁹P(O)(OR²¹)(OR²²), -JC(S)R²¹, -JNR²¹SO₂R²², -JNR⁹S(O)NR¹⁰R²²,-JNR⁹SO₂NR¹⁰R²², -JSO₂NR⁹COR²², -JSO₂NR⁹CONR²¹R²², -JNR²¹SO₂R²²,-JC(O)NR²¹SO₂R²², -JC(NH₂)═NR²², -JCH(NH₂)NR⁹S(O)₂R²², -JOC(O)NR²¹R²²,-JNR²¹C(O)OR²², -JNR²¹OC(O)R²², —(CH₂)₁₋₄C(O)NR²¹R²², -JNR⁹C(O)R²¹,-JC(O)R²¹, -JNR⁹C(O)NR¹⁰R²², —CCR²¹, —(CH₂)₁₋₄ OC(O)R²¹, and -JC(O)OR²³;R³⁵ is independently selected from the group consisting of naphthyl,naphthyloxy, indanyl, (4- to 7-membered heterocycloalkyl)C₀-C₄alkylcontaining 1 or 2 heteroatoms selected from N, O, and S, and bicyclicheterocycle containing 1, 2, or 3 heteroatoms independently selectedfrom N, O, and S, and containing 4- to 7- ring atoms in each ring; eachof which R³⁵ is unsubstituted or substituted with one or moresubstituents independently chosen from the group consisting of halogen,hydroxyl, nitro, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkanoyl,C₁-C₆alkoxy, (mono- and di-C₁-C₆alkylamino)C₀-C₄alkyl, C₁-C₆alkylester,—C₀-C₄alkyl(C₃-C₇cycloalkyl), —SO₂R⁹, C₁-C₂haloalkyl, andC₁-C₂haloalkoxy; R³⁶ is independently selected from the group consistingof tetrazolyl, (phenyl)C₀-C₂alkyl, (phenyl)C₁-C₂alkoxy, phenoxy, and 5-or 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independentlyselected from N, O, B, and S, each of which R³⁶ is unsubstituted orsubstituted with one or more substituents independently selected fromthe group consisting of halogen, hydroxyl, nitro, cyano, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkanoyl, C₁-C₆alkoxy, (mono- anddi-C₁-C₆alkylamino)C₀-C₄alkyl, C₁-C₆alkylester,—C₀-C₄alkyl(C₃-C₇cycloalkyl), —SO₂R⁹, —OSi(CH₃)₂C(CH₃)₃,—Si(CH₃)₂C(CH₃)₃, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy; R⁴⁸ isindependently selected from the group consisting of hydrogen, halogen,hydroxyl, nitro, cyano, amino, C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆thioalkyl, C₁-C₆alkoxy, -JC₃-C₇cycloalkyl, —B(OH)₂,-JC(O)NR⁹R²³, -JOSO₂OR²¹, —C(O)(CH₂)₁₋₄S(O)R²¹, —O(CH₂)₁₋₄S(O)NR²¹R²²,-JOP(O)(OR²¹)(OR²²), -JP(O)(OR²¹)(OR²²), -JOP(O)(OR²¹)R²²,-JP(O)(OR²¹)R²², -JOP(O)R²¹R²², -JP(O)R²¹R²², -JSP(O)(OR²¹)(OR²²),-JSP(O)(OR²¹)(R²²), -JSP(O)(R²¹)(R²²), -JNR⁹P(O)(NHR²¹)(NHR²²),-JNR⁹P(O)(OR²¹)(NHR²²), -JNR⁹P(O)(OR²¹)(OR²²), -JC(S)R²¹, -JNR²¹SO₂R²²,-JNR⁹S(O)NR¹⁰R²², -JNR⁹SO₂NR¹⁰R²², -JSO₂NR⁹COR²², -JSO₂NR⁹CONR²¹R²²,-JNR²¹SO₂R²², -JC(O)NR²¹SO₂R²², -JC(NH₂)═NR²², -JCH(NH₂)NR⁹S(O)₂R²²,-JOC(O)NR²¹R²², -JNR²¹C(O)OR²², -JNR²¹OC(O)R²², —(CH₂)₁₋₄ C(O)NR²¹R²²,-JNR⁹C(O)R²¹, -JC(O)R²¹, -JNR⁹C(O)NR¹⁰R²², —CCR²¹, —(CH₂)₁₋₄OC(O)R²¹,-JC(O)OR²³; and SC₁₋₆alkyl(O)═NH; R⁵² is independently selected from thegroup consisting of halo, hydrogen, and C₁-C₆alkyl; J is independentlyselected at each occurrence from the group consisting of a covalentbond, C₁-C₄alkylene, —OC₁-C₄alkylene, C₂-C₄alkenylene, andC₂-C₄alkynylene; R³⁷ is hydrogen, C₁-C₆alkyl, or—(C₀-C₂alkyl)(C₃-C₆cycloalkyl); R³⁸ and R³⁹ are independently selectedfrom the group consisting of hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆hydroxyalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy,(C₃-C₆cycloalkyl)C₀-C₄alkyl-, (aryl)C₀-C₂alkyl-, and(heteroaryl)C₀-C₂alkyl-; and wherein the disorder is selected fromnonalcoholic steatohepatitis (NASH), fatty liver, cirrhosis, liverfailure, amyotrophic lateral sclerosis, C3 glomerulonephritis,paroxysmal nocturnal hemoglobinuria (PNH), age-related maculardegeneration (AMD), and atypical hemolytic uremic syndrome.
 2. Themethod of claim 1, wherein the compound is of formula:

or a pharmaceutically acceptable salt thereof.
 3. The method of claim 1,wherein the compound is of formula:

or a pharmaceutically acceptable salt thereof.
 4. The method of claim 3,wherein B is B1.
 5. The method of claim 1, wherein B1 is selected fromthe group consisting of:


6. The method of claim 1, wherein R³² is selected from the groupconsisting of:


7. The method of claim 1, wherein B is phenyl or pyridyl substitutedwith 1, 2, or 3 substituents selected from the group consisting ofchloro, bromo, hydroxyl, C₁-C₂alkyl, C₁-C₂alkoxy, trifluoromethyl,phenyl, and trifluoromethoxy.
 8. The method of claim 1, wherein B is2-fluoro-3-chlorophenyl, or 2-fluoro-3-trifluoromethoxyphenyl.
 9. Themethod of claim 1, wherein B is pyridyl, optionally substituted withhalogen, C₁-C₂alkoxy, and trifluoromethyl.
 10. The method of claim 1,wherein R⁶ is selected from the group consisting of: —CHO, —C(O)NH₂,—C(O)NH(CH₃), C₂-C₆alkanoyl, and hydrogen.
 11. The method of claim 1,wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 12. The method of claim1, wherein the host is a human.
 13. The method of claim 1, wherein thedisorder is C3 glomerulonephritis.
 14. The method of claim 1, whereinthe disorder is PNH.
 15. The method of claim 1, wherein the disorder isNASH.
 16. The method of claim 1, wherein the disorder is fatty liver.17. The method of claim 1, wherein the disorder is cirrhosis.
 18. Themethod of claim 1, wherein the disorder is liver failure.
 19. The methodof claim 1, wherein the disorder is amyotrophic lateral sclerosis. 20.The method of claim 1, wherein the disorder is AMD.